5UKM
bovine GRK2 in complex with human Gbetagamma subunits and CCG258208 (14as)
Summary for 5UKM
| Entry DOI | 10.2210/pdb5ukm/pdb |
| 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, ... (7 entities in total) |
| Functional Keywords | kinase, inhibitor complex, transferase-signaling protein complex, transferase/signaling protein |
| Biological source | Bos taurus (Bovine) More |
| Total number of polymer chains | 3 |
| Total formula weight | 127585.99 |
| Authors | Cruz-Rodriguez, O.,Tesmer, J.J.G. (deposition date: 2017-01-23, release date: 2017-04-12, 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 Cited by 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: 28323425DOI: 10.1021/acs.jmedchem.7b00112 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.03 Å) |
Structure validation
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