PDBsum entry 5wg4

Transferase/signaling protein

PDB id: 5wg4

Contents

Protein chains

621 a.a.

339 a.a.

59 a.a.

Ligands

AFV

Waters ×143

PDB id:

5wg4

Name:

Transferase/signaling protein

Title:

Human grk2 in complex with gbetagamma subunits and ccg257284

Structure:

Beta-adrenergic receptor kinase 1. Chain: a. Synonym: beta-ark-1,g-protein coupled receptor kinase 2. Engineered: yes. Guanine nucleotide-binding protein g(i)/g(s)/g(t) subunit beta-1. Chain: b. Synonym: transducin beta chain 1. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: grk2, adrbk1, bark, bark1. Expressed in: trichoplusia. Expression_system_taxid: 7110. Bos taurus. Bovine. Organism_taxid: 9913.

Resolution:

2.31Å R-factor: 0.235 R-free: 0.279

Authors:

R.Bouley,J.J.G.Tesmer

Key ref:

R.Bouley et al. (2017). Structural Determinants Influencing the Potency and Selectivity of Indazole-Paroxetine Hybrid G Protein-Coupled Receptor Kinase 2 Inhibitors. Mol Pharmacol, 92, 707-717. PubMed id: 29070696

Date:

13-Jul-17 Release date: 27-Dec-17

Protein chain

P25098  (ARBK1_HUMAN) -  Beta-adrenergic receptor kinase 1 from Homo sapiens

Seq: 689 a.a.

Struc: 621 a.a.

Protein chain

P62871  (GBB1_BOVIN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 from Bos taurus

Seq: 340 a.a.

Struc: 339 a.a.

Protein chain

P63212  (GBG2_BOVIN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 from Bos taurus

Seq: 71 a.a.

Struc: 59 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

Mol Pharmacol 92:707-717 (2017)

PubMed id: 29070696

Structural Determinants Influencing the Potency and Selectivity of Indazole-Paroxetine Hybrid G Protein-Coupled Receptor Kinase 2 Inhibitors.

R.Bouley, H.V.Waldschmidt, M.C.Cato, A.Cannavo, J.Song, J.Y.Cheung, X.Q.Yao, W.J.Koch, S.D.Larsen, J.J.G.Tesmer.

ABSTRACT

G protein-coupled receptor kinases (GRKs) phosphorylate activated receptors to promote arrestin binding, decoupling from heterotrimeric G proteins, and internalization. GRK2 and GRK5 are overexpressed in the failing heart and thus have become therapeutic targets. Previously, we discovered two classes of GRK2-selective inhibitors, one stemming from GSK180736A, a Rho-associated coiled-coil containing kinase 1 (ROCK1) inhibitor, the other from paroxetine, a selective serotonin-reuptake inhibitor. These two classes of compounds bind to the GRK2 active site in a similar configuration but contain different hinge-binding "warheads": indazole and benzodioxole, respectively. We surmised from our prior studies that an indazole would be the stronger hinge binder and would impart increased potency when substituted for benzodioxole in paroxetine derivatives. To test this hypothesis, we synthesized a series of hybrid compounds that allowed us to compare the effects of inhibitors that differ only in the identity of the warhead. The indazole-paroxetine analogs were indeed more potent than their respective benzodioxole derivatives but lost selectivity. To investigate how these two warheads dictate selectivity, we determined the crystal structures of three of the indazole hybrid compounds (CCG224061, CCG257284, and CCG258748) in complex with GRK2-GβγComparison of these structures with those of analogous benzodioxole-containing complexes confirmed that the indazole-paroxetine hybrids form stronger interactions with the hinge of the kinase but also stabilize a distinct conformation of the kinase domain of GRK2 compared with previous complexes with paroxetine analogs. This conformation is analogous to one that can be assumed by GRK5, at least partially explaining the loss in selectivity.