Structure of a protease-activated GPCR
Figure: Structure of human PAR1
(blue) bound to the antagonist drug vorapaxar (green), with lipid (yellow)
and water (cyan) molecules.
Brian Kobilka group (Stanford University) and collaborators
Brian Kobilka's group published the first structure of a
protease-activated G protein-coupled receptor (GPCR). Protease-activated
receptor 1 (PAR1) is the prototypical member of a family of GPCRs that are
activated by proteases. The coagulation protease thrombin activates PAR1 by
specific cleavage of the receptor's N-terminal exodomain to generate a new
N-terminus. This new N-terminus then functions as a tethered peptide
agonist, binding intramolecularly to the seven-transmembrane bundle of the
receptor to effect G protein activation. Activation of PAR1 by thrombin
leads to platelet aggregation and thrombosis, and it has been considered as a
promising target for developing anti-platelet drugs for treating various
cardiovascular diseases. By using the T4 lysozyme insertion strategy, the
Kobilka group in collaboration with Shaun Coughlin's group at UCSF solved the
crystal structure of human PAR1 bound to an antagonist vorapaxar to
2.2-Å resolution. Vorapaxar is a promising drug candidate that has
been evaluated in two Phase 3 clinical trials. The structure reveals an
unusual ligand-binding mode of vorapaxar that explains how a small molecule
binds virtually irreversibly to inhibit receptor activation by the tethered
agonist peptide of PAR1. This structure will aid the development of improved
PAR1 antagonists and the discovery of antagonists to other members of the
protease-activated receptor family.
Zhang, C, Srinivasan, Y, Arlow, DH, Fung, JJ, Palmer, D, Zheng, Y, Green, HF,
Pandey, A, Dror, RO, Shaw, DE, Weis, WI, Coughlin, SR, Kobilka, BK.
High-resolution crystal structure of human protease-activated receptor 1,
Nature 492, 387-392 (2012).