Structure of RGS4 Bound to AlF4−-Activated Giα1: Stabilization of the Transition State for GTP Hydrolysis

Abstract RGS proteins are GTPase activators for heterotrimeric G proteins. We report here the 2.8 A resolution crystal structure of the RGS protein RGS4 complexed with G iα1 –Mg 2+ –GDP–AlF 4 − . Only the core domain of RGS4 is visible in the crystal. The core domain binds to the three switch regions of G iα1 , but does not contribute catalytic residues that directly interact with either GDP or AlF 4 − . Therefore, RGS4 appears to catalyze rapid hydrolysis of GTP primarily by stabilizing the switch regions of G iα1 , although the conserved Asn-128 from RGS4 could also play a catalytic role by interacting with the hydrolytic water molecule or the side chain of Gln-204. The binding site for RGS4 on G iα1 is also consistent with the activity of RGS proteins as antagonists of G α effectors.