1nc6
From Proteopedia
(New page: 200px<br /><applet load="1nc6" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nc6, resolution 1.90Å" /> '''Potent, small molecu...) |
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| - | [[Image:1nc6.gif|left|200px]]<br /><applet load="1nc6" size=" | + | [[Image:1nc6.gif|left|200px]]<br /><applet load="1nc6" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1nc6, resolution 1.90Å" /> | caption="1nc6, resolution 1.90Å" /> | ||
'''Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone'''<br /> | '''Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic | + | 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== | ==About this Structure== | ||
| - | 1NC6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with CA, SO4 and ABB as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] Full crystallographic information is available from [http:// | + | 1NC6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=ABB:'>ABB</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NC6 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Trypsin]] | [[Category: Trypsin]] | ||
| - | [[Category: Abraham, W | + | [[Category: Abraham, W M.]] |
[[Category: Andrade-Gordon, P.]] | [[Category: Andrade-Gordon, P.]] | ||
[[Category: Chattopadhyay, D.]] | [[Category: Chattopadhyay, D.]] | ||
| - | [[Category: Corcoran, T | + | [[Category: Corcoran, T W.]] |
| - | [[Category: Costanzo, M | + | [[Category: Costanzo, M J.]] |
| - | [[Category: Garavilla, L | + | [[Category: Garavilla, L de.]] |
| - | [[Category: Jr., H | + | [[Category: Jr., H R.Almond.]] |
| - | [[Category: Kauffman, J | + | [[Category: Kauffman, J A.]] |
| - | [[Category: Maryanoff, B | + | [[Category: Maryanoff, B E.]] |
[[Category: Recacha, R.]] | [[Category: Recacha, R.]] | ||
| - | [[Category: Yabut, S | + | [[Category: Yabut, S C.]] |
[[Category: ABB]] | [[Category: ABB]] | ||
[[Category: CA]] | [[Category: CA]] | ||
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[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:04:30 2008'' |
Revision as of 12:04, 21 February 2008
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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
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 with , and as ligands. Active as Trypsin, with EC number 3.4.21.4 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
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