5zk3: Difference between revisions
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The | ==Crystal structure of rationally thermostabilized M2 muscarinic acetylcholine receptor bound with QNB== | ||
<StructureSection load='5zk3' size='340' side='right' caption='[[5zk3]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5zk3]] 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=5ZK3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZK3 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=QNB:(3R)-1-AZABICYCLO[2.2.2]OCT-3-YL+HYDROXY(DIPHENYL)ACETATE'>QNB</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5xba|5xba]], [[5xbb|5xbb]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CHRM2 ([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=5zk3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zk3 OCA], [http://pdbe.org/5zk3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zk3 RCSB], [http://www.ebi.ac.uk/pdbsum/5zk3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zk3 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/ACM2_HUMAN ACM2_HUMAN]] Disease susceptibility is associated with variations affecting the gene represented in this entry. | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/ACM2_HUMAN ACM2_HUMAN]] The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human muscarinic receptor M2 is one of the five subtypes of muscarinic receptors belonging to the family of G-protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype-selective ligands against one of the five muscarinic receptors. We report high-resolution structures of a thermostabilized mutant M2 receptor bound to a subtype-selective antagonist AF-DX 384 and a nonselective antagonist NMS. The thermostabilizing mutation S110R in M2 was predicted using a theoretical strategy previously developed in our group. Comparison of the crystal structures and pharmacological properties of the M2 receptor shows that the Arg in the S110R mutant mimics the stabilizing role of the sodium cation, which is known to allosterically stabilize inactive state(s) of class A GPCRs. Molecular dynamics simulations reveal that tightening of the ligand-residue contacts in M2 receptors compared to M3 receptors leads to subtype selectivity of AF-DX 384. | |||
Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor.,Suno R, Lee S, Maeda S, Yasuda S, Yamashita K, Hirata K, Horita S, Tawaramoto MS, Tsujimoto H, Murata T, Kinoshita M, Yamamoto M, Kobilka BK, Vaidehi N, Iwata S, Kobayashi T Nat Chem Biol. 2018 Dec;14(12):1150-1158. doi: 10.1038/s41589-018-0152-y. Epub, 2018 Nov 12. PMID:30420692<ref>PMID:30420692</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5zk3" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Hirata, K]] | |||
[[Category: Horita, S]] | |||
[[Category: Iwata, S]] | |||
[[Category: Kinoshita, M]] | |||
[[Category: Kobayashi, T]] | |||
[[Category: Kobilka, B K]] | |||
[[Category: Maeda, S]] | |||
[[Category: Murata, T]] | |||
[[Category: Suno, R]] | |||
[[Category: Tawaramoto, M S]] | |||
[[Category: Tsujimoto, H]] | |||
[[Category: Yamamoto, M]] | |||
[[Category: Yamashita, K]] | |||
[[Category: Yasuda, S]] | |||
[[Category: Gpcr crystallography]] | |||
[[Category: Membrane protein-inhibitor complex]] | |||
[[Category: Rationally thermostabilized mutant]] | |||
Revision as of 23:50, 2 December 2018
Crystal structure of rationally thermostabilized M2 muscarinic acetylcholine receptor bound with QNBCrystal structure of rationally thermostabilized M2 muscarinic acetylcholine receptor bound with QNB
Structural highlights
Disease[ACM2_HUMAN] Disease susceptibility is associated with variations affecting the gene represented in this entry. Function[ACM2_HUMAN] The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Publication Abstract from PubMedHuman muscarinic receptor M2 is one of the five subtypes of muscarinic receptors belonging to the family of G-protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype-selective ligands against one of the five muscarinic receptors. We report high-resolution structures of a thermostabilized mutant M2 receptor bound to a subtype-selective antagonist AF-DX 384 and a nonselective antagonist NMS. The thermostabilizing mutation S110R in M2 was predicted using a theoretical strategy previously developed in our group. Comparison of the crystal structures and pharmacological properties of the M2 receptor shows that the Arg in the S110R mutant mimics the stabilizing role of the sodium cation, which is known to allosterically stabilize inactive state(s) of class A GPCRs. Molecular dynamics simulations reveal that tightening of the ligand-residue contacts in M2 receptors compared to M3 receptors leads to subtype selectivity of AF-DX 384. Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor.,Suno R, Lee S, Maeda S, Yasuda S, Yamashita K, Hirata K, Horita S, Tawaramoto MS, Tsujimoto H, Murata T, Kinoshita M, Yamamoto M, Kobilka BK, Vaidehi N, Iwata S, Kobayashi T Nat Chem Biol. 2018 Dec;14(12):1150-1158. doi: 10.1038/s41589-018-0152-y. Epub, 2018 Nov 12. PMID:30420692[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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