7EZC

Adenosine A2a receptor mutant-I92N

Summary for 7EZC

• Entry DOI: 10.2210/pdb7ezc/pdb
• Descriptor: Adenosine receptor A2a,Soluble cytochrome b562, 6-(2,2-diphenylethylamino)-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]-N-[2-[(1-pyridin-2-ylpiperidin-4-yl)carbamoylamino]ethyl]purine-2-carboxamide (2 entities in total)
• Functional Keywords: gpcr, adenosine, agonist, active mutation, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 97873.61

Authors

Cui, M.,Zhou, Q.,Yao, D.,Zhao, S.,Song, G. (deposition date: 2021-06-01, release date: 2022-04-13, Last modification date: 2024-11-20)

Primary citation

Cui, M.,Zhou, Q.,Xu, Y.,Weng, Y.,Yao, D.,Zhao, S.,Song, G.
Crystal structure of a constitutive active mutant of adenosine A 2A receptor.
Iucrj, 9:333-341, 2022

PubMed Abstract: The adenosine A receptor (AAR) is a prototypical member of the class A subfamily of G-protein-coupled receptors (GPCRs) that is widely distributed in various tissues and organs of the human body, and participates in many important signal-regulation processes. We have previously summarized a common activation pathway of class A GPCRs in which a series of conserved residues/motifs undergo conformational change during extracellular agonist binding and finally induce the coupling of intracellular G protein. Through this mechanism we have successfully predicted several novel constitutive active or inactive mutations for AAR. To reveal the molecular mechanism of mutation-induced constitutive activity, we determined the structure of a typical mutant I92N complexed with the agonist UK-432097. The mutated I92N forms a hydrophilic interaction network with nearby residues including Trp of the CWxP motif, which is absent in wild-type AAR. Although the mutant structure is similar overall to the previously determined intermediate-state AAR structure (PDB ID 3qak) [Xu, Wu, Katritch, Han, Jacobson, Gao, Cherezov & Stevens (2011). , , 322-327 ▸], molecular dynamics simulations suggest that the I92N mutant stabilizes the metastable intermediate state through the hydrophilic interaction network and favors the conformational transition of the receptor towards the active state. This research provides a structural template towards the special pharmacological outcome triggered by conformational mutation and sheds light on future structural or pharmaco-logical studies among class A GPCRs.

PubMed: 35546802
DOI: 10.1107/S2052252522001907

Experimental method

X-RAY DIFFRACTION (3.8 Å)