4tnb
From Proteopedia
Crystal Structure of G Protein-Coupled Receptor Kinase 5 in Complex with Sangivamycin
Structural highlights
FunctionGRK5_HUMAN Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).[1] [2] [3] [4] [5] Publication Abstract from PubMedG 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. Atomic Structure of G Protein-Coupled Receptor Kinase 5 (GRK5) Reveals Distinct Structural Features Novel for GRKs.,Komolov KE, Bhardwaj A, Benovic JL J Biol Chem. 2015 Jun 1. pii: jbc.M115.647297. PMID:26032409[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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