Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein-coupled Receptor Kinases
2015
Abstract G protein-coupled receptor kinases (GRKs) are members of the AGC kinase family and play a central role in mediating receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies including heart failure, hypertension, cancer and Alzheimers disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 angstrom resolution. GRK5 in complex with the ATP analog AMP-PNP or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly conserved feature that is divided into 3 segments: the C-lobe tether (CLT), the active-site tether (AST), and the N-lobe tether (NLT). This domain is fully resolved in GRK5 and reveals novel interactions with nucleotide and N-lobe. Similar to other AGC kinases, the GRK5 AST is an integral part of the nucleotide-binding pocket, a feature not observed in other GRKs. The AST also mediates contact between the kinase N- and C-lobes facilitating closure of the kinase domain. The GRK5 NLT is largely displaced from its previously observed position in other GRKs. Moreover, the autophosphorylation sites in the NLT are capable of rapid cis-autophosphorylation suggesting high mobility of this region. In summary, we provide a snapshot of GRK5 in a partially closed state, where structural elements of the kinase domain C-tail are aligned to form novel interactions to nucleotide and N-lobe not previously observed in other GRKs. These findings should be important in the design of selective drugs that target GRK5.
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