6kpc: Difference between revisions

Revision as of 11:43, 27 April 2022

Crystal structure of an agonist bound GPCR

Structural highlights

6kpc is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	E3R
Gene:	CNR2, CB2A, CB2B (HUMAN)
Activity:	Lysozyme, with EC number 3.2.1.17
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CNR2_HUMAN] Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.

Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures.,Hua T, Li X, Wu L, Iliopoulos-Tsoutsouvas C, Wang Y, Wu M, Shen L, Johnston CA, Nikas SP, Song F, Song X, Yuan S, Sun Q, Wu Y, Jiang S, Grim TW, Benchama O, Stahl EL, Zvonok N, Zhao S, Bohn LM, Makriyannis A, Liu ZJ Cell. 2020 Jan 28. pii: S0092-8674(20)30055-6. doi: 10.1016/j.cell.2020.01.008. PMID:32004463^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tao Q, McAllister SD, Andreassi J, Nowell KW, Cabral GA, Hurst DP, Bachtel K, Ekman MC, Reggio PH, Abood ME. Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity. Mol Pharmacol. 1999 Mar;55(3):605-13. PMID:10051546
↑ Feng W, Song ZH. Effects of D3.49A, R3.50A, and A6.34E mutations on ligand binding and activation of the cannabinoid-2 (CB2) receptor. Biochem Pharmacol. 2003 Apr 1;65(7):1077-85. PMID:12663043
↑ Kishimoto S, Gokoh M, Oka S, Muramatsu M, Kajiwara T, Waku K, Sugiura T. 2-arachidonoylglycerol induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism. J Biol Chem. 2003 Jul 4;278(27):24469-75. Epub 2003 Apr 23. PMID:12711605 doi:https://dx.doi.org/10.1074/jbc.M301359200
↑ Anand U, Otto WR, Sanchez-Herrera D, Facer P, Yiangou Y, Korchev Y, Birch R, Benham C, Bountra C, Chessell IP, Anand P. Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain. 2008 Sep 15;138(3):667-80. doi: 10.1016/j.pain.2008.06.007. Epub 2008 Aug, 9. PMID:18692962 doi:https://dx.doi.org/10.1016/j.pain.2008.06.007
↑ Hua T, Li X, Wu L, Iliopoulos-Tsoutsouvas C, Wang Y, Wu M, Shen L, Johnston CA, Nikas SP, Song F, Song X, Yuan S, Sun Q, Wu Y, Jiang S, Grim TW, Benchama O, Stahl EL, Zvonok N, Zhao S, Bohn LM, Makriyannis A, Liu ZJ. Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures. Cell. 2020 Jan 28. pii: S0092-8674(20)30055-6. doi: 10.1016/j.cell.2020.01.008. PMID:32004463 doi:https://dx.doi.org/10.1016/j.cell.2020.01.008

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Tao Q, McAllister SD, Andreassi J, Nowell KW, Cabral GA, Hurst DP, Bachtel K, Ekman MC, Reggio PH, Abood ME. Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity. Mol Pharmacol. 1999 Mar;55(3):605-13. PMID:10051546

[2] Feng W, Song ZH. Effects of D3.49A, R3.50A, and A6.34E mutations on ligand binding and activation of the cannabinoid-2 (CB2) receptor. Biochem Pharmacol. 2003 Apr 1;65(7):1077-85. PMID:12663043

[3] Kishimoto S, Gokoh M, Oka S, Muramatsu M, Kajiwara T, Waku K, Sugiura T. 2-arachidonoylglycerol induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism. J Biol Chem. 2003 Jul 4;278(27):24469-75. Epub 2003 Apr 23. PMID:12711605 doi:https://dx.doi.org/10.1074/jbc.M301359200

[4] Anand U, Otto WR, Sanchez-Herrera D, Facer P, Yiangou Y, Korchev Y, Birch R, Benham C, Bountra C, Chessell IP, Anand P. Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain. 2008 Sep 15;138(3):667-80. doi: 10.1016/j.pain.2008.06.007. Epub 2008 Aug, 9. PMID:18692962 doi:https://dx.doi.org/10.1016/j.pain.2008.06.007

[5] Hua T, Li X, Wu L, Iliopoulos-Tsoutsouvas C, Wang Y, Wu M, Shen L, Johnston CA, Nikas SP, Song F, Song X, Yuan S, Sun Q, Wu Y, Jiang S, Grim TW, Benchama O, Stahl EL, Zvonok N, Zhao S, Bohn LM, Makriyannis A, Liu ZJ. Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures. Cell. 2020 Jan 28. pii: S0092-8674(20)30055-6. doi: 10.1016/j.cell.2020.01.008. PMID:32004463 doi:https://dx.doi.org/10.1016/j.cell.2020.01.008

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[2]

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[5]

@@ Line 3: / Line 3: @@
 <StructureSection load='6kpc' size='340' side='right'caption='[[6kpc]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6kpc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KPC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KPC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6kpc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KPC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KPC FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8D0:(6~{a}~{R},9~{R},10~{a}~{R})-9-(hydroxymethyl)-3-(8-isothiocyanato-2-methyl-octan-2-yl)-6,6-dimethyl-6~{a},7,8,9,10,10~{a}-hexahydrobenzo[c]chromen-1-ol'>8D0</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E3R:7-[(6aR,9R,10aR)-1-Hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-+7-methyloctanenitrile'>E3R</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CNR2, CB2A, CB2B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CNR2, CB2A, CB2B ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </span></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </span></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=6kpc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kpc OCA], [http://pdbe.org/6kpc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kpc RCSB], [http://www.ebi.ac.uk/pdbsum/6kpc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kpc ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6kpc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kpc OCA], [https://pdbe.org/6kpc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kpc RCSB], [https://www.ebi.ac.uk/pdbsum/6kpc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kpc ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/CNR2_HUMAN CNR2_HUMAN]] Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis.<ref>PMID:10051546</ref> <ref>PMID:12663043</ref> <ref>PMID:12711605</ref> <ref>PMID:18692962</ref>
+[[https://www.uniprot.org/uniprot/CNR2_HUMAN CNR2_HUMAN]] Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis.<ref>PMID:10051546</ref> <ref>PMID:12663043</ref> <ref>PMID:12711605</ref> <ref>PMID:18692962</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

6kpc: Difference between revisions

Revision as of 11:43, 27 April 2022

Crystal structure of an agonist bound GPCR

Structural highlights

Function

Publication Abstract from PubMed

References

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