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Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3288-3293. doi: 10.1073/pnas.1809251116. Epub 2019 Feb 6.

Diverse GPCRs exhibit conserved water networks for stabilization and activation.

Venkatakrishnan AJ1,2,3,4, Ma AK1,2,3,4, Fonseca R3, Latorraca NR1,2,3,4,5, Kelly B1,2,3,4, Betz RM1,2,3,4,5, Asawa C1,2,3,4, Kobilka BK6, Dror RO7,2,3,4,5.

Author information

1
Department of Computer Science, Stanford University, Stanford, CA 94305.
2
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305.
3
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
4
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305.
5
Biophysics Program, Stanford University, Stanford, CA 94305.
6
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; kobilka@stanford.edu ron.dror@stanford.edu.
7
Department of Computer Science, Stanford University, Stanford, CA 94305; kobilka@stanford.edu ron.dror@stanford.edu.

Abstract

G protein-coupled receptors (GPCRs) have evolved to recognize incredibly diverse extracellular ligands while sharing a common architecture and structurally conserved intracellular signaling partners. It remains unclear how binding of diverse ligands brings about GPCR activation, the common structural change that enables intracellular signaling. Here, we identify highly conserved networks of water-mediated interactions that play a central role in activation. Using atomic-level simulations of diverse GPCRs, we show that most of the water molecules in GPCR crystal structures are highly mobile. Several water molecules near the G protein-coupling interface, however, are stable. These water molecules form two kinds of polar networks that are conserved across diverse GPCRs: (i) a network that is maintained across the inactive and the active states and (ii) a network that rearranges upon activation. Comparative analysis of GPCR crystal structures independently confirms the striking conservation of water-mediated interaction networks. These conserved water-mediated interactions near the G protein-coupling region, along with diverse water-mediated interactions with extracellular ligands, have direct implications for structure-based drug design and GPCR engineering.

KEYWORDS:

GPCR dynamics; activation; molecular dynamics simulation; polar network; water molecules

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