Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein-coupled Receptor Kinases

Abstract

Background: GRK5 is implicated in several human pathologies, but relatively little is known about its structure and function. Results: High resolution crystal structures of human GRK5 with AMP-PNP and sangivamycin were determined. Conclusion: GRK5 is found in a partially closed state with its kinase domain C-tail forming novel interactions with nucleotide and the N-lobe. Significance: The GRK5 structure provides important insight into its function.

Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4

“…5E). In contrast, the LXXDL motif that forms part of the interface between the RH domain and C-terminal region in GRK5 structures (30,31) is conserved in human GRK4 but not in rat or mouse GRK4 (Fig. 5E).…”

“…2) ever, sedimentation equilibrium experiments suggest that GRK4␣ is a monomer in solution, as seen also for GRK6 and GRK5 (26,31). Of the residues that form the core of a hydrophobic domain-swap dimer interface in the crystal structures of GRK6 and GRK1 (Fig.…”

“…Although it is not visible in the structure, GRK4␣ contains the LXXDL motif (Fig. 5E) that forms part of the same interface in two very recent crystal structures of GRK5 (30,31).…”

“…Three recent structures of GRK5 bound to AMPPNP, sangivamycin, and an inhibitor (CCG215022) are also in press (30,31). The lack of a GRK4 structure hinders understanding of GRK4 function in particular and of the GRK family in general.…”

“…E, alignment of residues in the RH domain (␣0-␣1 helix, ␣9 helix, and C-terminal end of ␣11 helix) that form a hydrophobic domain-swap interface in GRK6 and GRK1 crystal structures (26,27,41) or a C-terminal/RH domain packing interface within monomeric GRK5 structures (30,31). Conserved residues in the domain-swap interface of GRK6-AMPPNP (26) are highlighted in yellow, and those also interacting in the GRK5 monomer structures (30,31) are in green. The LXXDL motif (residues 534 -538 of human GRK5) is conserved in GRK4␣ as described previously (30) and is underlined.…”