Researchers using the LS-CAT 21-ID-D and GM/CA-XSD 23-ID-D beamlines at the APS have resolved the crystal structure of a human rhodopsin. This structure provides a basis for understanding G-protein-coupled receptors (GPCRs) signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology. The findings are reported in the journal Nature.
GPCRs are targets of one-third of the current clinically used drugs and comprise the largest family of cell surface receptors, which signal primarily via G proteins or arrestins. Upon activation, GPCRs recruit heterotrimeric G proteins and subsequently G-protein-coupled receptor kinases (GRKs), which phosphorylate GPCRs to allow the high-affinity binding to arrestin.
G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography.
Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin–arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ~20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.
Yanyong Kang, X. Edward Zhou, Xiang Gao, Yuanzheng He, Wei Liu, et al., “Crystal Structure of Rhodopsin Bound to Arrestin by Femtosecond X-ray Laser,” Nature, Article (2015), DOI: 10.1038/nature14656. Published Online July 22, 2015.