6C83
Structure of Aurora A (122-403) bound to inhibitory Monobody Mb2 and AMPPCP
Summary for 6C83
| Entry DOI | 10.2210/pdb6c83/pdb |
| Descriptor | Aurora kinase A, Mb2 Monobody, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER (3 entities in total) |
| Functional Keywords | transferase, aurora a, monobody, amppcp, kinase, activation, allostery, cell cycle, cancer, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 86699.90 |
| Authors | Hoemberger, M.,Kutter, S.,Zorba, A.,Nguyen, V.,Shohei, A.,Shohei, K.,Kern, D. (deposition date: 2018-01-24, release date: 2019-02-27, Last modification date: 2023-10-04) |
| Primary citation | Zorba, A.,Nguyen, V.,Koide, A.,Hoemberger, M.,Zheng, Y.,Kutter, S.,Kim, C.,Koide, S.,Kern, D. Allosteric modulation of a human protein kinase with monobodies. Proc.Natl.Acad.Sci.USA, 116:13937-13942, 2019 Cited by PubMed Abstract: Despite being the subject of intense effort and scrutiny, kinases have proven to be consistently challenging targets in inhibitor drug design. A key obstacle has been promiscuity and consequent adverse effects of drugs targeting the ATP binding site. Here we introduce an approach to controlling kinase activity by using monobodies that bind to the highly specific regulatory allosteric pocket of the oncoprotein Aurora A (AurA) kinase, thereby offering the potential for more specific kinase modulators. Strikingly, we identify a series of highly specific monobodies acting either as strong kinase inhibitors or activators via differential recognition of structural motifs in the allosteric pocket. X-ray crystal structures comparing AurA bound to activating vs inhibiting monobodies reveal the atomistic mechanism underlying allosteric modulation. The results reveal 3 major advantages of targeting allosteric vs orthosteric sites: extreme selectivity, ability to inhibit as well as activate, and avoidance of competing with ATP that is present at high concentrations in the cells. We envision that exploiting allosteric networks for inhibition or activation will provide a general, powerful pathway toward rational drug design. PubMed: 31239342DOI: 10.1073/pnas.1906024116 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.55 Å) |
Structure validation
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