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1nc6
From Proteopedia
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[[Image:1nc6.gif|left|200px]] | [[Image:1nc6.gif|left|200px]] | ||
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'''Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone''' | '''Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone''' | ||
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[[Category: Recacha, R.]] | [[Category: Recacha, R.]] | ||
[[Category: Yabut, S C.]] | [[Category: Yabut, S C.]] | ||
| - | [[Category: | + | [[Category: Protein-inhibitor complex]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:21:26 2008'' | |
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Revision as of 23:21, 2 May 2008
Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone
Overview
Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6 (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a K(i) value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (K(i) = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-A resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness.
About this Structure
1NC6 is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.
Reference
Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone., Costanzo MJ, Yabut SC, Almond HR Jr, Andrade-Gordon P, Corcoran TW, De Garavilla L, Kauffman JA, Abraham WM, Recacha R, Chattopadhyay D, Maryanoff BE, J Med Chem. 2003 Aug 28;46(18):3865-76. PMID:12930148 Page seeded by OCA on Sat May 3 02:21:26 2008
