PDBsum entry 4wnk

Ligase

PDB id: 4wnk

Contents

Protein chain

499 a.a.

Ligands

453

SO4

Waters ×37

PDB id:

4wnk

Name:

Ligase

Title:

Crystal structure of bovine g protein coupled-receptor kinase 5 in complex with ccg215022

Structure:

G protein-coupled receptor kinase 5. Chain: a. Synonym: g protein-coupled receptor kinase grk5. Engineered: yes

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Gene: grk5, gprk5. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.

Resolution:

2.42Å R-factor: 0.196 R-free: 0.243

Authors:

K.T.Homan,J.J.G.Tesmer

Key ref:

K.T.Homan et al. (2015). Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex with a Rationally Designed Inhibitor. J Biol Chem, 290, 20649-20659. PubMed id: 26032411 DOI: 10.1074/jbc.M115.647370

Date:

13-Oct-14 Release date: 10-Jun-15

Protein chain

P43249  (GRK5_BOVIN) -  G protein-coupled receptor kinase 5 from Bos taurus

Seq: 590 a.a.

Struc: 499 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.16 - [G-protein-coupled receptor] kinase.
• Reaction: [G-protein-coupled receptor] + ATP = [G-protein-coupled receptor]- phosphate + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.M115.647370

J Biol Chem 290:20649-20659 (2015)

PubMed id: 26032411

Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex with a Rationally Designed Inhibitor.

K.T.Homan, H.V.Waldschmidt, A.Glukhova, A.Cannavo, J.Song, J.Y.Cheung, W.J.Koch, S.D.Larsen, J.J.Tesmer.

ABSTRACT

G protein-coupled receptor kinases (GRKs) regulate cell signaling by initiating the desensitization of active G protein-coupled receptors. The two most widely expressed GRKs (GRK2 and GRK5) play a role in cardiovascular disease and thus represent important targets for the development of novel therapeutic drugs. In the course of a GRK2 structure-based drug design campaign, one inhibitor (CCG215022) exhibited nanomolar IC50 values against both GRK2 and GRK5 and good selectivity against other closely related kinases such as GRK1 and PKA. Treatment of murine cardiomyocytes with CCG215022 resulted in significantly increased contractility at 20-fold lower concentrations than paroxetine, an inhibitor with more modest selectivity for GRK2. A 2.4 Å crystal structure of the GRK5·CCG215022 complex was determined and revealed that the inhibitor binds in the active site similarly to its parent compound GSK180736A. As designed, its 2-pyridylmethyl amide side chain occupies the hydrophobic subsite of the active site where it forms three additional hydrogen bonds, including one with the catalytic lysine. The overall conformation of the GRK5 kinase domain is similar to that of a previously determined structure of GRK6 in what is proposed to be its active state, but the C-terminal region of the enzyme adopts a distinct conformation. The kinetic properties of site-directed mutants in this region are consistent with the hypothesis that this novel C-terminal structure is representative of the membrane-bound conformation of the enzyme.