1TFQ
NMR Structure of an Antagonists of the XIAP-Caspase-9 Interaction Complexed to the BIR3 domain of XIAP
Summary for 1TFQ
| Entry DOI | 10.2210/pdb1tfq/pdb |
| Related | 1TFT |
| Descriptor | Baculoviral IAP repeat-containing protein 4, ZINC ION, N-METHYLALANYL-3-METHYLVALYL-N-(1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)PROLINAMIDE (3 entities in total) |
| Functional Keywords | complex, ligand-protein, apoptosis, bir, xiap |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: P98170 |
| Total number of polymer chains | 1 |
| Total formula weight | 13932.95 |
| Authors | Oost, T.K.,Sun, C.,Armstrong, R.C.,Al-Assaad, A.S.,Betz, S.F.,Deckwerth, T.L.,Elmore, S.W.,Meadows, R.P.,Olejniczak, E.T.,Oleksijew, A.,Oltersdorf, T.,Rosenberg, S.H.,Shoemaker, A.R.,Zou, H.,Fesik, S.W. (deposition date: 2004-05-27, release date: 2004-09-07, Last modification date: 2024-05-22) |
| Primary citation | Oost, T.K.,Sun, C.,Armstrong, R.C.,Al-Assaad, A.S.,Betz, S.F.,Deckwerth, T.L.,Ding, H.,Elmore, S.W.,Meadows, R.P.,Olejniczak, E.T.,Oleksijew, A.,Oltersdorf, T.,Rosenberg, S.H.,Shoemaker, A.R.,Tomaselli, K.J.,Zou, H.,Fesik, S.W. Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer. J.Med.Chem., 47:4417-4426, 2004 Cited by PubMed Abstract: Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP. PubMed: 15317454DOI: 10.1021/jm040037k PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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