PDBsum entry 4pnk

Transferase/transferase inhibitor

PDB id: 4pnk

Contents

Protein chains

625 a.a.

339 a.a.

62 a.a.

Ligands

KZQ

Waters ×69

PDB id:

4pnk

Name:

Transferase/transferase inhibitor

Title:

G protein-coupled receptor kinase 2 in complex with gsk180736a

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: adrbk1, bark, bark1, grk2. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Gene: gnb1. Bos taurus. Bovine.

Resolution:

2.56Å R-factor: 0.194 R-free: 0.259

Authors:

K.T.Homan,K.M.Larimore,J.Elkins,S.Knapp,J.J.G.Tesmer

Key ref:

K.T.Homan et al. (2015). Identification and structure-function analysis of subfamily selective G protein-coupled receptor kinase inhibitors. Acs Chem Biol, 10, 310-319. PubMed id: 25238254 DOI: 10.1021/cb5006323

Date:

23-May-14 Release date: 08-Oct-14

Protein chain

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

Seq: 689 a.a.

Struc: 625 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

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

Seq: 71 a.a.

Struc: 62 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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/cb5006323

Acs Chem Biol 10:310-319 (2015)

PubMed id: 25238254

Identification and structure-function analysis of subfamily selective G protein-coupled receptor kinase inhibitors.

K.T.Homan, K.M.Larimore, J.M.Elkins, M.Szklarz, S.Knapp, J.J.Tesmer.

ABSTRACT

Selective inhibitors of individual subfamilies of G protein-coupled receptor kinases (GRKs) would serve as useful chemical probes as well as leads for therapeutic applications ranging from heart failure to Parkinson's disease. To identify such inhibitors, differential scanning fluorimetry was used to screen a collection of known protein kinase inhibitors that could increase the melting points of the two most ubiquitously expressed GRKs: GRK2 and GRK5. Enzymatic assays on 14 of the most stabilizing hits revealed that three exhibit nanomolar potency of inhibition for individual GRKs, some of which exhibiting orders of magnitude selectivity. Most of the identified compounds can be clustered into two chemical classes: indazole/dihydropyrimidine-containing compounds that are selective for GRK2 and pyrrolopyrimidine-containing compounds that potently inhibit GRK1 and GRK5 but with more modest selectivity. The two most potent inhibitors representing each class, GSK180736A and GSK2163632A, were cocrystallized with GRK2 and GRK1, and their atomic structures were determined to 2.6 and 1.85 Å spacings, respectively. GSK180736A, developed as a Rho-associated, coiled-coil-containing protein kinase inhibitor, binds to GRK2 in a manner analogous to that of paroxetine, whereas GSK2163632A, developed as an insulin-like growth factor 1 receptor inhibitor, occupies a novel region of the GRK active site cleft that could likely be exploited to achieve more selectivity. However, neither compound inhibits GRKs more potently than their initial targets. This data provides the foundation for future efforts to rationally design even more potent and selective GRK inhibitors.