2fv5
From Proteopedia
(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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| - | [[Image:2fv5.gif|left|200px]]<br /> | + | [[Image:2fv5.gif|left|200px]]<br /><applet load="2fv5" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2fv5" size=" | + | |
caption="2fv5, resolution 2.100Å" /> | caption="2fv5, resolution 2.100Å" /> | ||
'''Crystal structure of TACE in complex with IK682'''<br /> | '''Crystal structure of TACE in complex with IK682'''<br /> | ||
==Overview== | ==Overview== | ||
| - | TNFalpha converting enzyme (TACE) is the major metalloproteinase for the | + | 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== | ==About this Structure== | ||
| - | 2FV5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN and 541 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/ADAM_17_endopeptidase ADAM 17 endopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.86 3.4.24.86] Full crystallographic information is available from [http:// | + | 2FV5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=541:'>541</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/ADAM_17_endopeptidase ADAM 17 endopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.86 3.4.24.86] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FV5 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: tace adam17 zn-endopeptidase]] | [[Category: tace adam17 zn-endopeptidase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:25:23 2008'' |
Revision as of 15:25, 21 February 2008
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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 and 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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