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PDBsum entry 2fv5
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References listed in PDB file
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Key reference
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Title
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Ik682, A tight binding inhibitor of tace.
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Authors
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X.Niu,
S.Umland,
R.Ingram,
B.M.Beyer,
Y.H.Liu,
J.Sun,
D.Lundell,
P.Orth.
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Ref.
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Arch Biochem Biophys, 2006,
451,
43-50.
[DOI no: ]
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PubMed id
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Abstract
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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.
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