1TFQ

NMR Structure of an Antagonists of the XIAP-Caspase-9 Interaction Complexed to the BIR3 domain of XIAP

1TFQ の概要

• エントリーDOI: 10.2210/pdb1tfq/pdb
• 関連するPDBエントリー: 1TFT
• 分子名称: 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)
• 機能のキーワード: complex, ligand-protein, apoptosis, bir, xiap
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P98170
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13932.95

構造登録者

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. (登録日: 2004-05-27, 公開日: 2004-09-07, 最終更新日: 2024-05-22)

主引用文献

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

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: 15317454
DOI: 10.1021/jm040037k

実験手法

SOLUTION NMR