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bioRxiv · 10.1101/2021.01.18.427077

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

Jiang, Y.·Zhou, F.·Ye, C.·Ma, X.·Yin, W.·Zhou, Q.·He, X.·Zhang, X.·Croll, T. I.·Yang, D.·Wang, P.·Xu, H. E.·Wang, M.-W.
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Abstract

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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Jiang, Y., Zhou, F., Ye, C., Ma, X., Yin, W., Zhou, Q., He, X., Zhang, X., Croll, T. I., Yang, D., Wang, P., Xu, H. E., Wang, M.-W.. 2021-01-18. Molecular basis of ligand recognition and activation of human V2 vasopressin receptor. https://doi.org/10.1101/2021.01.18.427077

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