2FV5

Crystal structure of TACE in complex with IK682

2FV5 の概要

• エントリーDOI: 10.2210/pdb2fv5/pdb
• 関連するPDBエントリー: 1bkc 2ddf
• 分子名称: ADAM 17, ZINC ION, (2R)-N-HYDROXY-2-[(3S)-3-METHYL-3-{4-[(2-METHYLQUINOLIN-4-YL)METHOXY]PHENYL}-2-OXOPYRROLIDIN-1-YL]PROPANAMIDE, ... (4 entities in total)
• 機能のキーワード: tace adam17 zn-endopeptidase, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P78536
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59759.49

構造登録者

Orth, P.,Niu, X. (登録日: 2006-01-30, 公開日: 2006-07-04, 最終更新日: 2024-10-16)

主引用文献

Niu, X.,Umland, S.,Ingram, R.,Beyer, B.M.,Liu, Y.H.,Sun, J.,Lundell, D.,Orth, P.
IK682, a tight binding inhibitor of TACE.
Arch.Biochem.Biophys., 451:43-50, 2006

PubMed Abstract: TNFalpha converting enzyme (TACE) is the major metalloproteinase for the processing of TNFalpha, a key inflammatory cytokine. IK682, a hydroxamate compound, was reported to be a potent and specific TACE inhibitor [J.J. Duan, L. Chen, Z.R. Wasserman, Z. Lu, R.Q. Liu, M.B. Covington, M. Qian, K.D. Hardman, R.L. Magolda, R.C. Newton, D.D. Christ, R.R. Wexler, C.P. Decicco, J. Med. Chem. 45 (2002) 4954-4957]. The binding kinetics of IK682 and the ectodomain of human TACE was examined. The k(on) of IK682 was determined as 1.1+/-0.3 x 10(8) M(-1) min(-1). No detectable dissociation of IK682 from TACE was observed following dialysis, dilution, and extensive washing over a maximum of 72 h. This was in contrast to the rapid dissociation of IK682 from ADAM10. LC/MS analysis of the TACE-IK682 complex after dissociation under denaturing conditions indicated that the tight binding is not due to covalent interaction. The X-ray crystal structure of TACE-IK682 complex revealed multiple binding points at the S1' and S3' sites and the movement of a loop (from Ala349 to Gly442) to accommodate the binding of the quinolinyl group of IK682 at the S3' pocket. The conformational changes of TACE may contribute significantly to the high affinity binding as a result of a more stable TACE-inhibitor complex.

PubMed: 16762314
DOI: 10.1016/j.abb.2006.03.034

実験手法

X-RAY DIFFRACTION (2.1 Å)