2R9F
Calpain 1 proteolytic core inactivated by ZLAK-3002, an alpha-ketoamide
Summary for 2R9F
| Entry DOI | 10.2210/pdb2r9f/pdb |
| Related | 1kxr 1tl9 1tlo 2R9C 2g8e 2g8j |
| Descriptor | Calpain-1 catalytic subunit, CALCIUM ION, CHLORIDE ION, ... (6 entities in total) |
| Functional Keywords | protease, peptidase, inhibitor, alpha-ketoamide, hydrolase, membrane, thiol protease |
| Biological source | Rattus norvegicus (Rat) |
| Cellular location | Cytoplasm : P97571 |
| Total number of polymer chains | 1 |
| Total formula weight | 39694.93 |
| Authors | Qian, J.,Campbell, R.L.,Davies, P.L. (deposition date: 2007-09-12, release date: 2008-08-26, Last modification date: 2023-08-30) |
| Primary citation | Qian, J.,Cuerrier, D.,Davies, P.L.,Li, Z.,Powers, J.C.,Campbell, R.L. Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions. J.Med.Chem., 51:5264-5270, 2008 Cited by PubMed Abstract: Calpains are intracellular cysteine proteases that catalyze the cleavage of target proteins in response to Ca(2+) signaling. When Ca(2+) homeostasis is disrupted, calpain overactivation causes unregulated proteolysis, which can contribute to diseases such as postischemic injury and cataract formation. Potent calpain inhibitors exist, but of these many cross-react with other cysteine proteases and will need modification to specifically target calpain. Here, we present crystal structures of rat calpain 1 protease core (muI-II) bound to two alpha-ketoamide-based calpain inhibitors containing adenyl and piperazyl primed-side extensions. An unexpected aromatic-stacking interaction is observed between the primed-side adenine moiety and the Trp298 side chain. This interaction increased the potency of the inhibitor toward muI-II and heterodimeric m-calpain. Moreover, stacking orients the adenine such that it can be used as a scaffold for designing novel primed-side address regions, which could be incorporated into future inhibitors to enhance their calpain specificity. PubMed: 18702462DOI: 10.1021/jm800045t PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
Download full validation report
