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Molecular basis of ligand recognition and activation of human V2 vasopressin receptor

By Yi Jiang, Fulai Zhou, Chenyu Ye, Xiaomin Ma, Wanchao Yin, Qingtong Zhou, Xinheng He, Xiaokang Zhang, Tristan I Croll, Dehua Yang, Peiyi Wang, H. Eric Xu, Ming-Wei Wang

Posted 18 Jan 2021
bioRxiv DOI: 10.1101/2021.01.18.427077

The V2 vasopressin receptor (V2R) is a class A G protein-coupled receptor (GPCR) and plays a vital role in controlling water homeostasis upon stimulation by the natural peptide arginine vasopressin (AVP). Thus, V2R has attracted intense interest as a drug target for diabetes insipidus, nocturia, and hyponatremia. However, how AVP recognizes and activates V2R remains elusive. Here, we report the 2.6 [A] resolution structure of V2R bound to AVP and the stimulatory G protein Gs, determined by cryo-electron microscopy (cryo-EM). In this complex, AVP presents a unique cyclic conformation formed by an intramolecular disulfide bond and engages the orthosteric binding pocket of V2R in a ligand-specific mode. Comparison of the AVP-V2R-Gs complex to previously reported Gs-coupled class A GPCRs reveals distinct structural features, including a smaller outward movement of TM5 and TM6 and the concomitant shift of Gs protein. Our detailed structural analysis provides a framework for understanding AVP recognition and V2R activation, thereby offering a structural template for drug design targeting V2R.

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