8gus

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of HU-CB2-G protein complex

Structural highlights

8gus is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.97Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

Publication Abstract from PubMed

Cannabinoid CB(2) receptor (CB(2)R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB(2)R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB(2)R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB(2)R activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB(2)R activation by selective agonists and highlights the role of lipophilicity in CB(2)R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.

Structural basis of selective cannabinoid CB(2) receptor activation.,Li X, Chang H, Bouma J, de Paus LV, Mukhopadhyay P, Paloczi J, Mustafa M, van der Horst C, Kumar SS, Wu L, Yu Y, van den Berg RJBHN, Janssen APA, Lichtman A, Liu ZJ, Pacher P, van der Stelt M, Heitman LH, Hua T Nat Commun. 2023 Mar 15;14(1):1447. doi: 10.1038/s41467-023-37112-9. PMID:36922494^[3]

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

References

↑ 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
↑ Li X, Chang H, Bouma J, de Paus LV, Mukhopadhyay P, Paloczi J, Mustafa M, van der Horst C, Kumar SS, Wu L, Yu Y, van den Berg RJBHN, Janssen APA, Lichtman A, Liu ZJ, Pacher P, van der Stelt M, Heitman LH, Hua T. Structural basis of selective cannabinoid CB(2) receptor activation. Nat Commun. 2023 Mar 15;14(1):1447. PMID:36922494 doi:10.1038/s41467-023-37112-9

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8gus"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8gus]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GUS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GUS FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KO3:[(1~{S},4~{S},5~{S})-4-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-6,6-dimethyl-2-bicyclo[3.1.1]hept-2-enyl]methanol'>KO3</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]] 2.97&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KO3:[(1~{S},4~{S},5~{S})-4-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-6,6-dimethyl-2-bicyclo[3.1.1]hept-2-enyl]methanol'>KO3</scene></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=8gus FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gus OCA], [https://pdbe.org/8gus PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gus RCSB], [https://www.ebi.ac.uk/pdbsum/8gus PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gus ProSAT]</span></td></tr>
 </table>
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 8gus" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Transducin 3D structures|Transducin 3D structures]]
 == References ==
 <references/>

8gus

From Proteopedia

Current revision

Cryo-EM structure of HU-CB2-G protein complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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