2fv5
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(New page: 200px<br /> <applet load="2fv5" size="450" color="white" frame="true" align="right" spinBox="true" caption="2fv5, resolution 2.100Å" /> '''Crystal structure ...)
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Revision as of 20:04, 12 November 2007
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Crystal structure of TACE in complex with IK682
Overview
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.
About this Structure
2FV5 is a Single protein structure of sequence from Homo sapiens with ZN and 541 as ligands. Active as ADAM 17 endopeptidase, with EC number 3.4.24.86 Full crystallographic information is available from OCA.
Reference
IK682, a tight binding inhibitor of TACE., Niu X, Umland S, Ingram R, Beyer BM, Liu YH, Sun J, Lundell D, Orth P, Arch Biochem Biophys. 2006 Jul 1;451(1):43-50. Epub 2006 May 5. PMID:16762314
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