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6pt0

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Revision as of 07:15, 4 March 2020

Cryo-EM structure of human cannabinoid receptor 2-Gi protein in complex with agonist WIN 55,212-2

Structural highlights

6pt0 is a 5 chain structure with sequence from Human and Synthetic construct sequences. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	CNR2, CB2A, CB2B (HUMAN), GNAI1 (HUMAN), GNB1 (HUMAN), GNG2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [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] [GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.^[5] [GNAI1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.^[6] ^[7]

Publication Abstract from PubMed

Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-Gi signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and Gi coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.

Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex.,Xing C, Zhuang Y, Xu TH, Feng Z, Zhou XE, Chen M, Wang L, Meng X, Xue Y, Wang J, Liu H, McGuire TF, Zhao G, Melcher K, Zhang C, Xu HE, Xie XQ Cell. 2020 Jan 28. pii: S0092-8674(20)30054-4. doi: 10.1016/j.cell.2020.01.007. PMID:32004460^[8]

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:http://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:http://dx.doi.org/10.1016/j.pain.2008.06.007
↑ Johnston CA, Kimple AJ, Giguere PM, Siderovski DP. Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. Structure. 2008 Jul;16(7):1086-94. PMID:18611381 doi:http://dx.doi.org/10.1016/j.str.2008.04.010
↑ Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114
↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
↑ Xing C, Zhuang Y, Xu TH, Feng Z, Zhou XE, Chen M, Wang L, Meng X, Xue Y, Wang J, Liu H, McGuire TF, Zhao G, Melcher K, Zhang C, Xu HE, Xie XQ. Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex. Cell. 2020 Jan 28. pii: S0092-8674(20)30054-4. doi: 10.1016/j.cell.2020.01.007. PMID:32004460 doi:http://dx.doi.org/10.1016/j.cell.2020.01.007

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6pt0"

@@ Line 3: / Line 3: @@
 <StructureSection load='6pt0' size='340' side='right'caption='[[6pt0]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6pt0]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PT0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PT0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6pt0]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Synthetic_construct_sequences Synthetic construct sequences]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PT0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PT0 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=WI5:{(3R)-5-methyl-3-[(morpholin-4-yl)methyl]-2,3-dihydro[1,4]oxazino[2,3,4-hi]indol-6-yl}(naphthalen-1-yl)methanone'>WI5</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]), GNAI1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNG2 ([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=6pt0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pt0 OCA], [http://pdbe.org/6pt0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pt0 RCSB], [http://www.ebi.ac.uk/pdbsum/6pt0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pt0 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
+[[Category: Synthetic construct sequences]]
 [[Category: Chen, M]]
 [[Category: Feng, Z]]

6pt0

From Proteopedia

Revision as of 07:15, 4 March 2020

Cryo-EM structure of human cannabinoid receptor 2-Gi protein in complex with agonist WIN 55,212-2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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