5UKK

Human GRK2 in complex with human G-beta-gamma subunits and CCG211998 (14ak)

Summary for 5UKK

• Entry DOI: 10.2210/pdb5ukk/pdb
• Related: 5UKL
• Descriptor: Beta-adrenergic receptor kinase 1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: kinase, inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 118920.83

Authors

Cato, M.C.,Homan, K.T.,Tesmer, J.J.G. (deposition date: 2017-01-23, release date: 2017-04-05, Last modification date: 2023-10-04)

Primary citation

Waldschmidt, H.V.,Homan, K.T.,Cato, M.C.,Cruz-Rodriguez, O.,Cannavo, A.,Wilson, M.W.,Song, J.,Cheung, J.Y.,Koch, W.J.,Tesmer, J.J.,Larsen, S.D.
Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.
J. Med. Chem., 60:3052-3069, 2017

PubMed Abstract: In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart, making them desirable therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine, was previously identified as a GRK2 inhibitor. Utilizing a structure-based drug design approach, we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC of 30 nM against GRK2 and greater than 230-fold selectivity over other GRKs and kinases. Furthermore, 14as showed a 100-fold improvement in cardiomyocyte contractility assays over paroxetine and a plasma concentration higher than its IC for over 7 h. Three of these inhibitors, including 14as, were additionally crystallized in complex with GRK2 to give insights into the structural determinants of potency and selectivity of these inhibitors.

PubMed: 28323425
DOI: 10.1021/acs.jmedchem.7b00112

Experimental method

X-RAY DIFFRACTION (2.6 Å)