6w2y: Difference between revisions

Latest revision as of 11:21, 30 October 2024

CryoEM Structure of GABAB1b Homodimer

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.2Å
Ligands:	L9Q, MG, NAG, SGG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

GABA (gamma-aminobutyric acid) stimulation of the metabotropic GABAB receptor results in prolonged inhibition of neurotransmission that is central to brain physiology(1). GABAB belongs to the Family C of G protein-coupled receptors (GPCRs), which operate as dimers to relay synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins(2,3). GABAB, however, is unique in its function as an obligate heterodimer in which agonist binding and G protein activation take place on distinct subunits(4,5). Here we show structures of heterodimeric and homodimeric full-length GABAB receptors. Complemented by cellular signaling assays and atomistic simulations, the structures reveal an essential role for the GABAB extracellular loop 2 (ECL2) in relaying structural transitions by ordering the linker connecting the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of both GABAB subunits caps and interacts with the hydrophilic head of a phospholipid occupying the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G protein. These results provide a starting framework to decipher mechanistic modes of signal transduction mediated by GABAB dimers and have important implications for rational drug design targeting these receptors.

Structures of metabotropic GABAB receptor.,Papasergi-Scott MM, Robertson MJ, Seven AB, Panova O, Mathiesen JM, Skiniotis G Nature. 2020 Jun 24. pii: 10.1038/s41586-020-2469-4. doi:, 10.1038/s41586-020-2469-4. PMID:32580208^[1]

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

References

↑ Papasergi-Scott MM, Robertson MJ, Seven AB, Panova O, Mathiesen JM, Skiniotis G. Structures of metabotropic GABAB receptor. Nature. 2020 Jun 24. pii: 10.1038/s41586-020-2469-4. doi:, 10.1038/s41586-020-2469-4. PMID:32580208 doi:https://dx.doi.org/10.1038/s41586-020-2469-4

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OCA

[1] Papasergi-Scott MM, Robertson MJ, Seven AB, Panova O, Mathiesen JM, Skiniotis G. Structures of metabotropic GABAB receptor. Nature. 2020 Jun 24. pii: 10.1038/s41586-020-2469-4. doi:, 10.1038/s41586-020-2469-4. PMID:32580208 doi:https://dx.doi.org/10.1038/s41586-020-2469-4

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='6w2y' size='340' side='right'caption='[[6w2y]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6w2y]] is a 2 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=6W2Y OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W2Y FirstGlance]. <br>
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W2Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W2Y FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L9Q:(1S)-2-{[(S)-(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(OCTADECANOYLOXY)METHYL]ETHYL+(9Z)-OCTADEC-9-ENOATE'>L9Q</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SGG:[(2~{S})-3-[[(1~{S})-1-(3,4-dichlorophenyl)ethyl]amino]-2-oxidanyl-propyl]-(phenylmethyl)phosphinic+acid'>SGG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.2&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GABBR1, GPRC3A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L9Q:(1S)-2-{[(S)-(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(OCTADECANOYLOXY)METHYL]ETHYL+(9Z)-OCTADEC-9-ENOATE'>L9Q</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SGG:[(2~{S})-3-[[(1~{S})-1-(3,4-dichlorophenyl)ethyl]amino]-2-oxidanyl-propyl]-(phenylmethyl)phosphinic+acid'>SGG</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w2y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w2y OCA], [http://pdbe.org/6w2y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w2y RCSB], [http://www.ebi.ac.uk/pdbsum/6w2y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w2y 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=6w2y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w2y OCA], [https://pdbe.org/6w2y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w2y RCSB], [https://www.ebi.ac.uk/pdbsum/6w2y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w2y ProSAT]</span></td></tr>
 </table>
-== Function ==
-[[http://www.uniprot.org/uniprot/GABR1_HUMAN GABR1_HUMAN]] Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Calcium is required for high affinity binding to GABA. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception. Activated by (-)-baclofen, cgp27492 and blocked by phaclofen.<ref>PMID:9844003</ref> <ref>PMID:9872316</ref> <ref>PMID:18165688</ref> <ref>PMID:22660477</ref>   Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites.<ref>PMID:9844003</ref> <ref>PMID:9872316</ref> <ref>PMID:18165688</ref> <ref>PMID:22660477</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Papasergi-Scott, M M]]
+[[Category: Papasergi-Scott MM]]
-[[Category: Robertson, M J]]
+[[Category: Robertson MJ]]
-[[Category: Skiniotis, G]]
+[[Category: Skiniotis G]]
-[[Category: Gpcr]]
-[[Category: Homodimer]]
-[[Category: Inhibitor]]
-[[Category: Signaling protein]]

6w2y: Difference between revisions

Latest revision as of 11:21, 30 October 2024

CryoEM Structure of GABAB1b Homodimer

Structural highlights

Publication Abstract from PubMed

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