1ayv: Difference between revisions

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==Overview==
==Overview==
Potent and selective active-site-spanning inhibitors have been designed, for cathepsin K, a cysteine protease unique to osteoclasts. They act by, mechanisms that involve tight binding intermediates, potentially on a, hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and, kinetic studies of the mechanisms of inhibition indicate that different, intermediates or transition states are being represented that are, dependent on the conditions of measurement and the specific groups, flanking the carbonyl in the inhibitor. The species observed, crystallographically are most consistent with tetrahedral intermediates, that may be close approximations of those that occur during substrate, hydrolysis. Initial kinetic studies suggest the possibility of, irreversible and reversible active-site modification. Representative, inhibitors have demonstrated antiresorptive activity both in vitro and in, vivo and therefore are promising leads for therapeutic agents for the, treatment of osteoporosis. Expansion of these inhibitor concepts can be, envisioned for the many other cysteine proteases implicated for, therapeutic intervention.
Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.


==Disease==
==Disease==
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
[[Category: Abdel-Meguid, S.S.]]
[[Category: Abdel-Meguid, S S.]]
[[Category: Janson, C.A.]]
[[Category: Janson, C A.]]
[[Category: Smith, W.W.]]
[[Category: Smith, W W.]]
[[Category: Zhao, B.]]
[[Category: Zhao, B.]]
[[Category: IN6]]
[[Category: IN6]]
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[[Category: sulfhydryl proteinase]]
[[Category: sulfhydryl proteinase]]


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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:49:41 2008''

Revision as of 12:49, 21 February 2008

File:1ayv.jpg


1ayv, resolution 2.3Å

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CRYSTAL STRUCTURE OF CYSTEINE PROTEASE HUMAN CATHEPSIN K IN COMPLEX WITH A COVALENT THIAZOLHYDRAZIDE INHIBITOR

OverviewOverview

Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.

DiseaseDisease

Known disease associated with this structure: Pycnodysostosis OMIM:[601105]

About this StructureAbout this Structure

1AYV is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Cathepsin K, with EC number 3.4.22.38 Full crystallographic information is available from OCA.

ReferenceReference

Design of potent and selective human cathepsin K inhibitors that span the active site., Thompson SK, Halbert SM, Bossard MJ, Tomaszek TA, Levy MA, Zhao B, Smith WW, Abdel-Meguid SS, Janson CA, D'Alessio KJ, McQueney MS, Amegadzie BY, Hanning CR, DesJarlais RL, Briand J, Sarkar SK, Huddleston MJ, Ijames CF, Carr SA, Garnes KT, Shu A, Heys JR, Bradbeer J, Zembryki D, Lee-Rykaczewski L, James IE, Lark MW, Drake FH, Gowen M, Gleason JG, Veber DF, Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14249-54. PMID:9405598

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