1nc6: Difference between revisions

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[[Image:1nc6.gif|left|200px]]<br /><applet load="1nc6" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

[[Image:1nc6.gif|left|200px]]<br /><applet load="1nc6" size="350" color="white" frame="true" align="right" spinBox="true"

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 />

==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.

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 [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://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1NC6 OCA].

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==

Line 14:

[[Category: Single protein]]

[[Category: Trypsin]]

[[Category: Abraham, W.M.]]

[[Category: Abraham, W M.]]

[[Category: Andrade-Gordon, P.]]

[[Category: Chattopadhyay, D.]]

[[Category: Corcoran, T.W.]]

[[Category: Corcoran, T W.]]

[[Category: Costanzo, M.J.]]

[[Category: Costanzo, M J.]]

[[Category: Garavilla, L.de.]]

[[Category: Garavilla, L de.]]

[[Category: Jr., H.R.Almond.]]

[[Category: Jr., H R.Almond.]]

[[Category: Kauffman, J.A.]]

[[Category: Kauffman, J A.]]

[[Category: Maryanoff, B.E.]]

[[Category: Maryanoff, B E.]]

[[Category: Recacha, R.]]

[[Category: Yabut, S.C.]]

[[Category: Yabut, S C.]]

[[Category: ABB]]

[[Category: CA]]

Line 30:

[[Category: protein-inhibitor complex]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Tue Nov 20 22~~:07:~~51 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:04:30 2008''

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@@ Line 1: / Line 1: @@
-[[Image:1nc6.gif|left|200px]]<br /><applet load="1nc6" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1nc6.gif|left|200px]]<br /><applet load="1nc6" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1nc6, resolution 1.90&Aring;" />
 '''Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone'''<br />
 ==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.
+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==
-NC6 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NC6 OCA].
+NC6 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==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Trypsin]]
-[[Category: Abraham, W.M.]]
+[[Category: Abraham, W M.]]
 [[Category: Andrade-Gordon, P.]]
 [[Category: Chattopadhyay, D.]]
-[[Category: Corcoran, T.W.]]
+[[Category: Corcoran, T W.]]
-[[Category: Costanzo, M.J.]]
+[[Category: Costanzo, M J.]]
-[[Category: Garavilla, L.de.]]
+[[Category: Garavilla, L de.]]
-[[Category: Jr., H.R.Almond.]]
+[[Category: Jr., H R.Almond.]]
-[[Category: Kauffman, J.A.]]
+[[Category: Kauffman, J A.]]
-[[Category: Maryanoff, B.E.]]
+[[Category: Maryanoff, B E.]]
 [[Category: Recacha, R.]]
-[[Category: Yabut, S.C.]]
+[[Category: Yabut, S C.]]
 [[Category: ABB]]
 [[Category: CA]]
@@ Line 30: / Line 30: @@
 [[Category: protein-inhibitor complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 22:07:51 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:04:30 2008''