Proteopedia - User contributions [en]

User:Dotan Shaniv/Sandbox 1

2017-07-15T21:27:38Z

Dotan Shaniv:

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>
== Overview ==
See the topic [[Beta-2_Adrenergic_Receptor|Beta-2 Adrenergic Receptor]].
== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Since this is a representation of a protein has been crystallized in a lipid environment, the majority of the chains contains <scene name='76/761789/Hydrophobic_residues/1'>hydrophobic residues</scene>.

Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
Beta-adrenergic receptors are [[G_protein-coupled_receptor|G Protein-Coupled Receptors]], i.e. their action of catecholamine-induced activation of [[adenylate cyclase]] is mediated through the action of [[GTP-binding_protein|G proteins]]. Beta-2-adrenergic receptors are widely distributed in the respiratory tract and are found on many types of cells there, such as smooth muscle cells, epithelial and endothelial cells, mast cells and more<ref>PMID: 16387578</ref>. The natural ligands for adrenoceptors are epinephrine\norepinephrine (it may be worth noting that the beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine). When these ligands bind to adrenoceptors they activate them (they are their natural agonists), which in the case of the beta-2-adrenergic receptor translates to the sympathetic effect in the respiratory tract, namely, bronchodilation. This is the reason that beta-2-adrenergic receptors are the main target in [http://en.wikipedia.org/wiki/Asthma Asthma] treatment - drugs that function as beta-2 agonists help to activate these receptors in a similar way to epinephrine\norepinephrine and help patients to deal with acute or chronic asthma symptoms.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from [[rhodopsin]] in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

User:Dotan Shaniv/Sandbox 1

2017-07-15T21:26:19Z

Dotan Shaniv:

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>
== Overview ==
See the topic [[Beta-2_Adrenergic_Receptor|Beta-2 Adrenergic Receptor]].
== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Since this protein has been crystallized in a lipid environment, the majority of the chains contains <scene name='76/761789/Hydrophobic_residues/1'>hydrophobic residues</scene>.

Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
Beta-adrenergic receptors are [[G_protein-coupled_receptor|G Protein-Coupled Receptors]], i.e. their action of catecholamine-induced activation of [[adenylate cyclase]] is mediated through the action of [[GTP-binding_protein|G proteins]]. Beta-2-adrenergic receptors are widely distributed in the respiratory tract and are found on many types of cells there, such as smooth muscle cells, epithelial and endothelial cells, mast cells and more<ref>PMID: 16387578</ref>. The natural ligands for adrenoceptors are epinephrine\norepinephrine (it may be worth noting that the beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine). When these ligands bind to adrenoceptors they activate them (they are their natural agonists), which in the case of the beta-2-adrenergic receptor translates to the sympathetic effect in the respiratory tract, namely, bronchodilation. This is the reason that beta-2-adrenergic receptors are the main target in [http://en.wikipedia.org/wiki/Asthma Asthma] treatment - drugs that function as beta-2 agonists help to activate these receptors in a similar way to epinephrine\norepinephrine and help patients to deal with acute or chronic asthma symptoms.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from [[rhodopsin]] in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

User:Dotan Shaniv/Sandbox 1

2017-07-15T21:25:30Z

Dotan Shaniv: Hydrophobic residues

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>
== Overview ==
See the topic [[Beta-2_Adrenergic_Receptor|Beta-2 Adrenergic Receptor]].
== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Since this protein has been crystallized in a lipid environment, the majority of the chains contains <scene name='76/761789/Hydrophobic_residues/1'>hydrophobic residues</scene>.

ull crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
Beta-adrenergic receptors are [[G_protein-coupled_receptor|G Protein-Coupled Receptors]], i.e. their action of catecholamine-induced activation of [[adenylate cyclase]] is mediated through the action of [[GTP-binding_protein|G proteins]]. Beta-2-adrenergic receptors are widely distributed in the respiratory tract and are found on many types of cells there, such as smooth muscle cells, epithelial and endothelial cells, mast cells and more<ref>PMID: 16387578</ref>. The natural ligands for adrenoceptors are epinephrine\norepinephrine (it may be worth noting that the beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine). When these ligands bind to adrenoceptors they activate them (they are their natural agonists), which in the case of the beta-2-adrenergic receptor translates to the sympathetic effect in the respiratory tract, namely, bronchodilation. This is the reason that beta-2-adrenergic receptors are the main target in [http://en.wikipedia.org/wiki/Asthma Asthma] treatment - drugs that function as beta-2 agonists help to activate these receptors in a similar way to epinephrine\norepinephrine and help patients to deal with acute or chronic asthma symptoms.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from [[rhodopsin]] in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

User:Dotan Shaniv/Sandbox 1

2017-07-13T06:54:47Z

Dotan Shaniv:

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>
== Overview ==
See the topic [[Beta-2_Adrenergic_Receptor|Beta-2 Adrenergic Receptor]].
== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
Beta-adrenergic receptors are [[G_protein-coupled_receptor|G Protein-Coupled Receptors]], i.e. their action of catecholamine-induced activation of [[adenylate cyclase]] is mediated through the action of [[GTP-binding_protein|G proteins]]. Beta-2-adrenergic receptors are widely distributed in the respiratory tract and are found on many types of cells there, such as smooth muscle cells, epithelial and endothelial cells, mast cells and more<ref>PMID: 16387578</ref>. The natural ligands for adrenoceptors are epinephrine\norepinephrine (it may be worth noting that the beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine). When these ligands bind to adrenoceptors they activate them (they are their natural agonists), which in the case of the beta-2-adrenergic receptor translates to the sympathetic effect in the respiratory tract, namely, bronchodilation. This is the reason that beta-2-adrenergic receptors are the main target in [http://en.wikipedia.org/wiki/Asthma Asthma] treatment - drugs that function as beta-2 agonists help to activate these receptors in a similar way to epinephrine\norepinephrine and help patients to deal with acute or chronic asthma symptoms.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from [[rhodopsin]] in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

User:Dotan Shaniv/Sandbox 1

2017-07-12T21:34:12Z

Dotan Shaniv:

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>
== Overview ==
See the topic [[Beta-2_Adrenergic_Receptor|Beta-2 Adrenergic Receptor]].
== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
Beta-adrenergic receptors are [[G_protein-coupled_receptor|G Protein-Coupled Receptors]], i.e. they mediate the catecholamine-induced activation of [[adenylate cyclase]] through the action of [[GTP-binding_protein|G proteins]]. The beta-2-adrenergic receptor is widely distributed in the respiratory tract and is found on many types of cells there, such as smooth muscle cells, epithelial and endothelial cells, mast cells and more<ref>PMID: 16387578</ref>. The natural ligands for adrenoceptors are epinephrine\norepinephrine (it may be worth noting that the beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine). When these ligands bind to adrenoceptors they activate them (they are their natural agonists), which in the case of the beta-2-adrenergic receptor translates to the sympathetic effect in the respiratory tract, namely, bronchodilation. This is the reason that beta-2-adrenergic receptors are the main target in [http://en.wikipedia.org/wiki/Asthma Asthma] treatment - drugs that function as beta-2 agonists help to activate these receptors in a similar way to epinephrine\norepinephrine and help patients to deal with acute or chronic asthma symptoms.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from [[rhodopsin]] in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

User:Dotan Shaniv/Sandbox 1

2017-07-12T21:30:21Z

Dotan Shaniv:

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>
== Overview ==
See the topic [[Beta-2_Adrenergic_Receptor|Beta-2 Adrenergic Receptor]].
== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
Beta-adrenergic receptors are [[G_protein-coupled_receptor|G Protein-Coupled Receptors]], i.e. they mediate the catecholamine-induced activation of [[adenylate cyclase]] through the action of [[GTP-binding_protein|G proteins]]. The beta-2-adrenergic receptor is widely distributed in the respiratory tract and is found on many types of cells there, such as smooth muscle cells, epithelial and endothelial cells, mast cells and more<ref>PMID: 16387578</ref>. The natural ligands for adrenoceptors are epinephrine\norepinephrine (it may be worth noting that the beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine). When these ligands bind to adrenoceptors they activate them (they are their natural agonists), which in the case of the beta-2-adrenergic receptor translates to the sympathetic effect in the respiratory tract, namely, bronchodilation. This is the reason that beta-2-adrenergic receptors are the main target in [http://en.wikipedia.org/wiki/Asthma Asthma] treatment - drugs that function as beta-2 agonists help to activate these receptors in a similar way to epinephrine\norepinephrine and help patients to deal with acute or chronic asthma symptoms.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

User:Dotan Shaniv/Sandbox 1

2017-07-12T20:41:34Z

Dotan Shaniv:

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>

== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/ADRB2_HUMAN ADRB2_HUMAN]] Beta-adrenergic receptors are [[G_protein-coupled_receptor|G Protein-Coupled Receptors]], i.e. they mediate the catecholamine-induced activation of [[adenylate cyclase]] through the action of [[GTP-binding_protein|G proteins]]. The beta-2-adrenergic receptor is widely distributed in the respiratory tract and is found on many types of cells there, such as smooth muscle cells, epithelial and endothelial cells, mast cells and more<ref>PMID: 16387578</ref>. The natural ligands for adrenoceptors are epinephrine\norepinephrine (it may be worth noting that the beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine). When these ligands bind to adrenoceptors they activate them (i.e. they are their natural agonists), which in the case of the beta-2-adrenergic receptor translates to the sympathetic effect in the respiratory tract, namely, bronchodilation. This is the reason that the beta-2-adrenergic receptor is the main target in [http://en.wikipedia.org/wiki/Asthma Asthma] treatment - drugs that function as beta-2 agonists help to activate these receptors and allow patients to deal with acute or chronic asthma symptoms.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

User:Dotan Shaniv/Sandbox 1

2017-07-12T20:27:00Z

Dotan Shaniv: New page: ==Crystal structure of the human beta2 adrenoceptor== <StructureSection load='2r4s' size='340' side='right' caption='2r4s, resolution 3.40Å' scene=''> == Structur...

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>

== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/ADRB2_HUMAN ADRB2_HUMAN]] Beta-adrenergic receptors are [[G_protein-coupled_receptor|G Protein-Coupled Receptors]], i.e. they mediate the catecholamine-induced activation of [[adenylate cyclase]] through the action of [[GTP-binding_protein|G proteins]]. The beta-2-adrenergic receptor is widely distributed in the respiratory tract and is found on many types of cells there, such as smooth muscle cells, epithelial and endothelial cells, mast cells and more<ref>PMID: 16387578</ref>. binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

Elizeu/sandbox/citocromo c

2017-07-12T18:54:22Z

Dotan Shaniv: Removing all content from page

User:Dotan Shaniv

2017-07-12T18:51:58Z

Dotan Shaniv:

*[[User:Dotan Shaniv/Sandbox 1]]
* Full Real Name: Dotan Shaniv

* Position: MSc student of chemistry

* Institution (NO ABBREVIATIONS): Weizmann Institute of Science

* City, State/Province, Country: Rehovot, Israel

* Field of Expertise or Study: Pharmacology, pharmaceutical sciences as a bachelor in pharmacy. Now starting MSc studies at the Chemistry faculty in Weizmann Institute of Science in Israel. Exposed to the project via prof. Joel Sussman from the institute.

Elizeu/sandbox/citocromo c

2017-07-12T18:47:20Z

Dotan Shaniv:

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>

== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/ADRB2_HUMAN ADRB2_HUMAN]] Beta-adrenergic receptors are [[G Protein-Coupled Receptors]], which means that they mediate the catecholamine-induced activation of [[adenylate cyclase]] through the action of [[G proteins]]. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

Elizeu/sandbox/citocromo c

2017-07-12T18:44:43Z

Dotan Shaniv:

==Crystal structure of the human beta2 adrenoceptor==
<StructureSection load='2r4s' size='340' side='right' caption='[[2r4s]], [[Resolution|resolution]] 3.40Å' scene=''>

== Structural highlights ==
<table><tr><td colspan='2'>[[2r4s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R4S FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r4r|2r4r]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4s OCA], [http://pdbe.org/2r4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2r4s RCSB], [http://www.ebi.ac.uk/pdbsum/2r4s PDBsum]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/ADRB2_HUMAN ADRB2_HUMAN]] Beta-adrenergic receptors are [[G_protein-coupled_receptors]] mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
<jmolCheckbox>
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4s_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.,Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK Nature. 2007 Nov 15;450(7168):383-7. Epub 2007 Oct 21. PMID:17952055<ref>PMID:17952055</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2r4s" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adrenergic receptor|Adrenergic receptor]]
*[[G protein-coupled receptor|G protein-coupled receptor]]
*[[Monoclonal Antibody|Monoclonal Antibody]]
*[[Nobel Prizes for 3D Molecular Structure|Nobel Prizes for 3D Molecular Structure]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mus musculus]]
[[Category: Burghammer, M]]
[[Category: Choi, H J]]
[[Category: Edwards, P C]]
[[Category: Fischetti, R F]]
[[Category: Kobilka, B K]]
[[Category: Kobilka, T S]]
[[Category: Rasmussen, S G.F]]
[[Category: Ratnala, V R]]
[[Category: Rosenbaum, D M]]
[[Category: Sanishvili, R]]
[[Category: Schertler, G F]]
[[Category: Thian, F S]]
[[Category: Weis, W I]]
[[Category: G-protein coupled receptor]]
[[Category: Glycoprotein]]
[[Category: Lipoprotein]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Receptor]]
[[Category: Signaling protein]]
[[Category: Transducer]]
[[Category: Transmembrane helix]]

Beta-2 Adrenergic Receptor

2017-07-12T18:39:02Z

Dotan Shaniv:

<StructureSection load='2rh1' size='490' side='right' caption='Solved Structure of a Beta 2-Adrenergic Receptor, ([[2rh1]])' scene='Beta-2_Adrenergic_Receptor/Opening/1' >
[[Image:B2ar Image3.png|200px|left]]       [[Beta-2 Adrenergic Receptor]]'''s''' (B2ARs) are a type of [[G protein-coupled receptor|G Protein-Coupled Receptor (GPCR)]]. GPCRs are the largest family of integral membrane proteins in the human body with over 1000 unique Isoforms. B2AR is activated by hormone ligands like adrenaline (epinephrine) and noradrenaline and plays a critical role in cardiovascular and pulmonary physiology. Binding of adrenaline by B2AR causes a sympathetic nervous system response like the well-known “fight or flight response”, resulting in an increased heart rate, pupil dilation, rapid energy mobilization and diversion of blood to skeletal muscle. More precisely, upon binding a ligand, B2AR activates [[Adenylyl cyclase]] through interaction with B2ARs C-terminus. Adenylyl cyclase subsequently converts ATP into cAMP, which functions as a downstream signaling molecule activating effectors like cAMP-dependent protein kinases, resulting in various bodily responses.<ref name="Witter"/>

====B2AR and Autism====
      During embryo development, Beta adrenergic receptors are involved in fetal growth, tissue differentiation and axonal outgrowth. During fetus development, B2AR transcription is progressively downregulated and undergoes desensitization. These steps are essential homeostatic mechanisms to prevent cells from being overly stimulated and maintaining the correct sympathetic to parasympathetic tone. This sympathetic-parasympathetic tone determines the point at which the sympathetic nervous system (flight or fight) overrides the parasympathetic nervous system (responsible for normal cardiovascular homeostasis). The B2AR downregulation and desensitization steps are first established during prenatal development during the first and second trimester.<ref name="Witter">PMID: 19961985</ref> Interestingly, overstimulation of B2ARs during critical periods of prenatal development can cause a permanent increase in the sympathetic to parasympathetic tone. Overstimulation of this type is caused by stress in the mother for reasons ranging from infections to hardships like natural disasters. Since children with autism typically have an elevated sympathetic tone and elevated B2AR stimulation during development causes an elevated sympathetic tone, this partly explains why children of mothers who survive natural disasters during pregnancy have a higher incidence of [[Autism Spectrum Disorders]] (ASDs).<ref name="Witter"/>

====Fevers and the Locus Coeruleus====
      As an aside, stress during prenatal development has also been proven to impact locus coeruelus (LC) development. Nearly all adrenaline in the brain is produced and transported by neurons in the Locus Coeruleous, a small area of the brain. The locus coeruleus-Noradrenergic System (LC-NA) plays a crucial role in virtually all aspects of behavioral adaptations and performance of cognitive regions of the brain commonly affected in ASDs.<ref name="Purpura">PMID: 19059284</ref> Critical enzymes for proper LC can be downregulated by aberrant epigenetic modifications caused by prenatal stress. One well known example of this is hypomethylation of the Crh gene. When methylated, the Crh promotor is bound by the transcriptional repressor, [[MeCP2]]. Aberrant epigenetic modifications caused by prenatal stress can cause Crh promoters to be under methylated, preventing MeCp2 binding and subsequently causing overexpression of the Crh gene. Overexpression of the Crh gene is a trademark of Rett Syndrome, a well known [[Neurodevelopmental Disorders|neurodevelopmental disorder]] Interestingly, when some autism patients have a fever, the LC-NA system dysfunction abates resulting in reduced autistic behaviors. This implies that the underlying neural networks mediating the LC-NA system are still functional, and offers hope for partial reversal of ASDs through [[Pharmaceutical Drugs|pharmaceutical intervention]].<ref name="Purpura"/>

====Structure of B2ARs====
      As a family, GPCRs are renowned for their structure solution difficulty. In this model, Beta2-Adrenergic Receptor (B2AR) – T4 Lysozyme fusion was developed to allow for structure solution. Fortunately, the <scene name='Beta-2_Adrenergic_Receptor/Opening_lyso/1'>lysozyme portion</scene> of the structure does not appear to impact the structure of the B2AR. The structure of B2AR is very similar to the GPCR [[Rhodopsin]], which is a photoreceptor in the retina which allows the perception of light. B2AR is a transmembrane protein with <scene name='Beta-2_Adrenergic_Receptor/Helices/1'>7 transmembrane helices</scene> and an 8th helix which runs parallel to the cytoplasmic face of the membrane.<ref name="Rasmussen">PMID: 17952055</ref> Helices 2,5,6 and 7 of B2AR have <scene name='Beta-2_Adrenergic_Receptor/Kinks/1'>kinks caused by prolines</scene> at conserved places, which are important for activation of G protein effectors. The <scene name='Beta-2_Adrenergic_Receptor/Extracellular_residues/1'>extracellular regions</scene> on all GPCRs dictate the ligand specificity of GPCRs. The partial inverse agonist, Carazolol, <scene name='Beta-2_Adrenergic_Receptor/Cara_binding/1'>binds to the receptor binding pocket</scene> of B2AR, reducing the basal activity of the receptor. This interaction involves residues Tyr 199, Ser 203, Ser 207, Phe 193, Ser 204, Ser 293, Phe 290, Tyr 308, Phe 289, Asn 312, Tyr 316, Trp 286, Trp 109 and Asp 113. Carazolol occupies a similar position as the rhodopsin inverse agonist, retinal. Carazolol does not act with the so called “toggle switch” on helix 6, but does interact with Phe 290, causing <scene name='Beta-2_Adrenergic_Receptor/Cara_binding_w/1'>Trp 286 to assume an inactive rotameric state</scene>, effectively inhibiting B2AR activity.<ref>PMID: 17962520</ref> A <scene name='Beta-2_Adrenergic_Receptor/Dry/1'>conserved DRY motif</scene> (residues 130-132) is present in all GPCRs.<ref>PMID: 18547522</ref> In rhodopsin, the Arginine in this motif forms a salt bridge with a glutamate, an interaction that maintains rhodopsin in its inactive state until it is exposed to light. In B2AR, Arg 131 <scene name='Beta-2_Adrenergic_Receptor/Dry_no_salt/1'>does not interact with Glu 268</scene>, which helps explain why B2AR has basal activity. Interestingly, Rhodopsin has no basil activity, a feature that is critical for vision.<ref>PMID: 18818650</ref>

====Pharmaceutical Implications====
      Although activation of B2AR upon ligand binding is not fully understood, a recently solved structure of Beta 1 Adrenergic Receptors offers clues. Agonists of B1ARs <scene name='Beta-2_Adrenergic_Receptor/Disrupted/1'>disrupt the interaction</scene> ([[2y02]]) between Val 172 and Ser 215, eliminating a key interaction between helices four and five. Since mutation to Val 172 is known to reduce basal activity, it is likely that the agonists interference of Val 172 has a similar affect.<ref>PMID: 21228877</ref> The class of [[Pharmaceutical Drugs|pharmaceutical drugs]] known as the “beta blockers” are antagonists of B2AR. They diminish the effects of adrenaline, slowing the heart rhythm and reducing blood pressure. B2AR Agonists serve a completely different purpose. These molecules which mimic native ligands of B2AR cause smooth muscle relaxation, bronchial passage dilation, vasodilation and rapid release of insulin. These compounds are used to treat asthma, and include the well-known Albuterol and Terbutaline.<ref>PMID: 20692524</ref>
__NOTOC__
__NOEDITSECTION__
</StructureSection>

==3D structures of beta-2 adrenergic receptor==
<table width=309' align='right' cellpadding='0'><tr><td rowspan='2'> </td><td bgcolor='#eeeeee'>[[Image:7tm labeled.png|right|300px]]</td></tr><tr><td bgcolor='#eeeeee'><center>
β2 adrenergic receptor binding a hormone analog<br/> and complexed to a heterotrimeric G protein ([[3sn6]])
</center></td></tr></table>
{{Template:GPCR3sn6}}
[[Adrenergic receptor]]

{{Template:Robert and Kobilka Nobel Prize}}

==References==
<references/>

==See Also==
* [[G protein-coupled receptor]]
* [[Adrenergic receptor]]
* [[Group:SMART:A Physical Model of the β2-Adrenergic Receptor|The Madison West High School 2008 SMART Team's Page on the β-2 adrenergic receptor]]
* [[Nobel Prizes for 3D Molecular Structure]]
* [[Highest impact structures]] of all time
* [[GTP-binding protein| G proteins]]
*[[Rhodopsin]]
* [[GTP-binding protein]]
*[[Pharmaceutical Drugs]]
*[[Membrane proteins]]
*[[Hormone]]

==External Resources==
* [http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/ Robert J. Lefkowitz and Brian K. Kobilka share the 2012 Nobel Prize in Chemistry] for work on GPCRs that includes solving the first structures of a ligand-activated GPCR (2007) and the first activated GPCR in complex with its G protein (2011). A detailed description of the laureates' body of work on this class of receptors with images is [http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/popular-chemistryprize2012.pdf here].
* The April 2008 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Adrenergic Receptors'' by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2008_4 10.2210/rcsb_pdb/mom_2008_4].

==Page Development==
This article was initially developed based on lectures given in Chemistry 543 by Prof. Clarence E. Schutt at Princeton University.

Beta-2 Adrenergic Receptor

2017-07-12T18:34:33Z

Dotan Shaniv:

<StructureSection load='2rh1' size='490' side='right' caption='Solved Structure of a Beta 2-Adrenergic Receptor, ([[2rh1]])' scene='Beta-2_Adrenergic_Receptor/Opening/1' >
[[Image:B2ar Image3.png|200px|left]]       [[Beta-2 Adrenergic Receptor]]'''s''' (B2ARs) are a type of [[G protein-coupled receptor|G Protein-Coupled Receptor (GPCR)]]. GPCRs are the largest family of integral membrane proteins in the human body with over 1000 unique Isoforms. B2AR is activated by hormone ligands like adrenaline (epinephrine) and noradrenaline and plays a critical role in cardiovascular and pulmonary physiology. Binding of adrenaline by B2AR causes a sympathetic nervous system response like the well-known “fight or flight response”, resulting in an increased heart rate, pupil dilation, rapid energy mobilization and diversion of blood to skeletal muscle. More precisely, upon binding a ligand, B2AR activates [[Adenylyl cyclase]] through interaction with B2ARs C-terminus. Adenylyl cyclase subsequently converts ATP into cAMP, which functions as a downstream signaling molecule activating effectors like cAMP-dependent protein kinases, resulting in various bodily responses.<ref name="Witter"/>

====B2AR and Autism====
      During embryo development, Beta adrenergic receptors are involved in fetal growth, tissue differentiation and axonal outgrowth. During fetus development, B2AR transcription is progressively downregulated and undergoes desensitization. These steps are essential homeostatic mechanisms to prevent cells from being overly stimulated and maintaining the correct sympathetic to parasympathetic tone. This sympathetic-parasympathetic tone determines the point at which the sympathetic nervous system (flight or fight) overrides the parasympathetic nervous system (responsible for normal cardiovascular homeostasis). The B2AR downregulation and desensitization steps are first established during prenatal development during the first and second trimester.<ref name="Witter">PMID: 19961985</ref> Interestingly, overstimulation of B2ARs during critical periods of prenatal development can cause a permanent increase in the sympathetic to parasympathetic tone. Overstimulation of this type is caused by stress in the mother for reasons ranging from infections to hardships like natural disasters. Since children with autism typically have an elevated sympathetic tone and elevated B2AR stimulation during development causes an elevated sympathetic tone, this partly explains why children of mothers who survive natural disasters during pregnancy have a higher incidence of [[Autism Spectrum Disorders]] (ASDs).<ref name="Witter"/>

====Fevers and the Locus Coeruleus====
      As an aside, stress during prenatal development has also been proven to impact locus coeruelus (LC) development. Nearly all adrenaline in the brain is produced and transported by neurons in the Locus Coeruleous, a small area of the brain. The locus coeruleus-Noradrenergic System (LC-NA) plays a crucial role in virtually all aspects of behavioral adaptations and performance of cognitive regions of the brain commonly affected in ASDs.<ref name="Purpura">PMID: 19059284</ref> Critical enzymes for proper LC can be downregulated by aberrant epigenetic modifications caused by prenatal stress. One well known example of this is hypomethylation of the Crh gene. When methylated, the Crh promotor is bound by the transcriptional repressor, [[MeCP2]]. Aberrant epigenetic modifications caused by prenatal stress can cause Crh promoters to be under methylated, preventing MeCp2 binding and subsequently causing overexpression of the Crh gene. Overexpression of the Crh gene is a trademark of Rett Syndrome, a well known [[Neurodevelopmental Disorders|neurodevelopmental disorder]] Interestingly, when some autism patients have a fever, the LC-NA system dysfunction abates resulting in reduced autistic behaviors. This implies that the underlying neural networks mediating the LC-NA system are still functional, and offers hope for partial reversal of ASDs through [[Pharmaceutical Drugs|pharmaceutical intervention]].<ref name="Purpura"/>

====Strucutre of B2ARs====
      As a family, GPCRs are renowned for their structure solution difficulty. In this model, Beta2-Adrenergic Receptor (B2AR) – T4 Lysozyme fusion was developed to allow for structure solution. Fortunately, the <scene name='Beta-2_Adrenergic_Receptor/Opening_lyso/1'>lysozyme portion</scene> of the structure does not appear to impact the structure of the B2AR. The structure of B2AR is very similar to the GPCR [[Rhodopsin]], which is a photoreceptor in the retina which allows the perception of light. B2AR is a transmembrane protein with <scene name='Beta-2_Adrenergic_Receptor/Helices/1'>7 transmembrane helices</scene> and an 8th helix which runs parallel to the cytoplasmic face of the membrane.<ref name="Rasmussen">PMID: 17952055</ref> Helices 2,5,6 and 7 of B2AR have <scene name='Beta-2_Adrenergic_Receptor/Kinks/1'>kinks caused by prolines</scene> at conserved places, which are important for activation of G protein effectors. The <scene name='Beta-2_Adrenergic_Receptor/Extracellular_residues/1'>extracellular regions</scene> on all GPCRs dictate the ligand specificity of GPCRs. The partial inverse agonist, Carazolol, <scene name='Beta-2_Adrenergic_Receptor/Cara_binding/1'>binds to the receptor binding pocket</scene> of B2AR, reducing the basal activity of the receptor. This interaction involves residues Tyr 199, Ser 203, Ser 207, Phe 193, Ser 204, Ser 293, Phe 290, Tyr 308, Phe 289, Asn 312, Tyr 316, Trp 286, Trp 109 and Asp 113. Carazolol occupies a similar position as the rhodopsin inverse agonist, retinal. Carazolol does not act with the so called “toggle switch” on helix 6, but does interact with Phe 290, causing <scene name='Beta-2_Adrenergic_Receptor/Cara_binding_w/1'>Trp 286 to assume an inactive rotameric state</scene>, effectively inhibiting B2AR activity.<ref>PMID: 17962520</ref> A <scene name='Beta-2_Adrenergic_Receptor/Dry/1'>conserved DRY motif</scene> (residues 130-132) is present in all GPCRs.<ref>PMID: 18547522</ref> In rhodopsin, the Arginine in this motif forms a salt bridge with a glutamate, an interaction that maintains rhodopsin in its inactive state until it is exposed to light. In B2AR, Arg 131 <scene name='Beta-2_Adrenergic_Receptor/Dry_no_salt/1'>does not interact with Glu 268</scene>, which helps explain why B2AR has basal activity. Interestingly, Rhodopsin has no basil activity, a feature that is critical for vision.<ref>PMID: 18818650</ref>

====Pharmaceutical Implications====
      Although activation of B2AR upon ligand binding is not fully understood, a recently solved structure of Beta 1 Adrenergic Receptors offers clues. Agonists of B1ARs <scene name='Beta-2_Adrenergic_Receptor/Disrupted/1'>disrupt the interaction</scene> ([[2y02]]) between Val 172 and Ser 215, eliminating a key interaction between helices four and five. Since mutation to Val 172 is known to reduce basal activity, it is likely that the agonists interference of Val 172 has a similar affect.<ref>PMID: 21228877</ref> The class of [[Pharmaceutical Drugs|pharmaceutical drugs]] known as the “beta blockers” are antagonists of B2AR. They diminish the effects of adrenaline, slowing the heart rhythm and reducing blood pressure. B2AR Agonists serve a completely different purpose. These molecules which mimic native ligands of B2AR cause smooth muscle relaxation, bronchial passage dilation, vasodilation and rapid release of insulin. These compounds are used to treat asthma, and include the well-known Albuterol and Terbutaline.<ref>PMID: 20692524</ref>
__NOTOC__
__NOEDITSECTION__
</StructureSection>

==3D structures of beta-2 adrenergic receptor==
<table width=309' align='right' cellpadding='0'><tr><td rowspan='2'> </td><td bgcolor='#eeeeee'>[[Image:7tm labeled.png|right|300px]]</td></tr><tr><td bgcolor='#eeeeee'><center>
β2 adrenergic receptor binding a hormone analog<br/> and complexed to a heterotrimeric G protein ([[3sn6]])
</center></td></tr></table>
{{Template:GPCR3sn6}}
[[Adrenergic receptor]]

{{Template:Robert and Kobilka Nobel Prize}}

==References==
<references/>

==See Also==
* [[G protein-coupled receptor]]
* [[Adrenergic receptor]]
* [[Group:SMART:A Physical Model of the β2-Adrenergic Receptor|The Madison West High School 2008 SMART Team's Page on the β-2 adrenergic receptor]]
* [[Nobel Prizes for 3D Molecular Structure]]
* [[Highest impact structures]] of all time
* [[GTP-binding protein| G proteins]]
*[[Rhodopsin]]
* [[GTP-binding protein]]
*[[Pharmaceutical Drugs]]
*[[Membrane proteins]]
*[[Hormone]]

==External Resources==
* [http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/ Robert J. Lefkowitz and Brian K. Kobilka share the 2012 Nobel Prize in Chemistry] for work on GPCRs that includes solving the first structures of a ligand-activated GPCR (2007) and the first activated GPCR in complex with its G protein (2011). A detailed description of the laureates' body of work on this class of receptors with images is [http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/popular-chemistryprize2012.pdf here].
* The April 2008 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Adrenergic Receptors'' by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2008_4 10.2210/rcsb_pdb/mom_2008_4].

==Page Development==
This article was initially developed based on lectures given in Chemistry 543 by Prof. Clarence E. Schutt at Princeton University.