PDBsum entry 5he0

Transferase/transferase inhibitor

PDB id: 5he0

Contents

Protein chains

621 a.a.

339 a.a.

60 a.a.

Ligands

453

Waters ×36

PDB id:

5he0

Name:

Transferase/transferase inhibitor

Title:

Bovine grk2 in complex with gbetagamma subunits and ccg215022

Structure:

Beta-adrenergic receptor kinase 1. Chain: a. Fragment: unp residues 30-670. Synonym: beta-ark-1, g-protein-coupled receptor kinase 2. Engineered: yes. Mutation: yes. Guanine nucleotide-binding protein g(i)/g(s)/g(t) subunit beta-1. Chain: b.

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Gene: adrbk1, grk2. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Homo sapiens. Human. Organism_taxid: 9606.

Resolution:

2.56Å R-factor: 0.205 R-free: 0.264

Authors:

M.C.Cato,J.Waninger-Saroni,J.J.G.Tesmer

Key ref:

H.V.Waldschmidt et al. (2016). Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors. J Med Chem, 59, 3793-3807. PubMed id: 27050625 DOI: 10.1021/acs.jmedchem.5b02000

Date:

05-Jan-16 Release date: 11-May-16

Protein chain

P21146  (ARBK1_BOVIN) -  Beta-adrenergic receptor kinase 1 from Bos taurus

Seq: 689 a.a.

Struc: 621 a.a.

Protein chain

P62873  (GBB1_HUMAN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 from Homo sapiens

Seq: 340 a.a.

Struc: 339 a.a.

Protein chain

P59768  (GBG2_HUMAN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 from Homo sapiens

Seq: 71 a.a.

Struc: 60 a.a.

Enzyme reactions

• Enzyme class: Chain A: E.C.2.7.11.15 - [beta-adrenergic-receptor] kinase.
• Reaction: [beta-adrenergic receptor] + ATP = [beta-adrenergic receptor]-phosphate + ADP + H⁺

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

reference

DOI no: 10.1021/acs.jmedchem.5b02000

J Med Chem 59:3793-3807 (2016)

PubMed id: 27050625

Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors.

H.V.Waldschmidt, K.T.Homan, O.Cruz-Rodríguez, M.C.Cato, J.Waninger-Saroni, K.M.Larimore, A.Cannavo, J.Song, J.Y.Cheung, P.D.Kirchhoff, W.J.Koch, J.J.Tesmer, S.D.Larsen.

ABSTRACT

G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compounds possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound, 12n (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kinase selectivity of this class of inhibitors.