1d1v

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(New page: 200px<br /><applet load="1d1v" size="450" color="white" frame="true" align="right" spinBox="true" caption="1d1v, resolution 1.93&Aring;" /> '''BOVINE ENDOTHELIAL N...)
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[[Image:1d1v.gif|left|200px]]<br /><applet load="1d1v" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1d1v, resolution 1.93&Aring;" />
caption="1d1v, resolution 1.93&Aring;" />
'''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH S-ETHYL-N-PHENYL-ISOTHIOUREA (H4B BOUND)'''<br />
'''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH S-ETHYL-N-PHENYL-ISOTHIOUREA (H4B BOUND)'''<br />
==Overview==
==Overview==
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Nitric oxide produced by nitric-oxide synthase (NOS) is not only involved, in a wide range of physiological functions but also in a variety of, pathological conditions. Isoform-selective NOS inhibitors are highly, desirable to regulate the NO production of one isoform beneficial to, normal physiological functions from the uncontrolled NO production of, another isoform that accompanies certain pathological states. Crystal, structures of the heme domain of the three NOS isoforms have revealed a, very high degree of similarity in the immediate vicinity of the heme, active site illustrating the challenge of isoform-selective inhibitor, design. Isothioureas are potent NOS inhibitors, and the structures of the, endothelial NOS heme domain complexed with isothioureas bearing small, S-alkyl substituents have been determined (Li, H., Raman, C.S., Martasek, P., Kral, V., Masters, B.S.S., and Poulos, T.L. (2000) J. Inorg. Biochem., 81, 133--139). In the present communication, the binding mode of larger, bisisothioureas complexed to the endothelial NOS heme domain has been, determined. These structures afford a structural rationale for the known, inhibitory activities. In addition, these structures provide clues on how, to exploit the longer inhibitor substituents that extend out of the active, site pocket for isoform-selective inhibitor design.
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Nitric oxide produced by nitric-oxide synthase (NOS) is not only involved in a wide range of physiological functions but also in a variety of pathological conditions. Isoform-selective NOS inhibitors are highly desirable to regulate the NO production of one isoform beneficial to normal physiological functions from the uncontrolled NO production of another isoform that accompanies certain pathological states. Crystal structures of the heme domain of the three NOS isoforms have revealed a very high degree of similarity in the immediate vicinity of the heme active site illustrating the challenge of isoform-selective inhibitor design. Isothioureas are potent NOS inhibitors, and the structures of the endothelial NOS heme domain complexed with isothioureas bearing small S-alkyl substituents have been determined (Li, H., Raman, C.S., Martasek, P., Kral, V., Masters, B.S.S., and Poulos, T.L. (2000) J. Inorg. Biochem. 81, 133--139). In the present communication, the binding mode of larger bisisothioureas complexed to the endothelial NOS heme domain has been determined. These structures afford a structural rationale for the known inhibitory activities. In addition, these structures provide clues on how to exploit the longer inhibitor substituents that extend out of the active site pocket for isoform-selective inhibitor design.
==About this Structure==
==About this Structure==
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1D1V 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 ACT, ZN, HEM, H4B, PTU, CAD and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1D1V OCA].
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1D1V 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=ACT:'>ACT</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=HEM:'>HEM</scene>, <scene name='pdbligand=H4B:'>H4B</scene>, <scene name='pdbligand=PTU:'>PTU</scene>, <scene name='pdbligand=CAD:'>CAD</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D1V OCA].
==Reference==
==Reference==
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[[Category: Li, H.]]
[[Category: Li, H.]]
[[Category: Martasek, P.]]
[[Category: Martasek, P.]]
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[[Category: Masters, B.S.S.]]
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[[Category: Masters, B S.S.]]
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[[Category: Poulos, T.L.]]
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[[Category: Poulos, T L.]]
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[[Category: Raman, C.S.]]
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[[Category: Raman, C S.]]
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[[Category: Southan, G.J.]]
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[[Category: Southan, G J.]]
[[Category: ACT]]
[[Category: ACT]]
[[Category: CAD]]
[[Category: CAD]]
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[[Category: oxidoreductase]]
[[Category: oxidoreductase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 12:56:35 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:12:05 2008''

Revision as of 10:12, 21 February 2008

Image:1d1v.gif

1d1v, resolution 1.93Å

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BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH S-ETHYL-N-PHENYL-ISOTHIOUREA (H4B BOUND)

Overview

Nitric oxide produced by nitric-oxide synthase (NOS) is not only involved in a wide range of physiological functions but also in a variety of pathological conditions. Isoform-selective NOS inhibitors are highly desirable to regulate the NO production of one isoform beneficial to normal physiological functions from the uncontrolled NO production of another isoform that accompanies certain pathological states. Crystal structures of the heme domain of the three NOS isoforms have revealed a very high degree of similarity in the immediate vicinity of the heme active site illustrating the challenge of isoform-selective inhibitor design. Isothioureas are potent NOS inhibitors, and the structures of the endothelial NOS heme domain complexed with isothioureas bearing small S-alkyl substituents have been determined (Li, H., Raman, C.S., Martasek, P., Kral, V., Masters, B.S.S., and Poulos, T.L. (2000) J. Inorg. Biochem. 81, 133--139). In the present communication, the binding mode of larger bisisothioureas complexed to the endothelial NOS heme domain has been determined. These structures afford a structural rationale for the known inhibitory activities. In addition, these structures provide clues on how to exploit the longer inhibitor substituents that extend out of the active site pocket for isoform-selective inhibitor design.

About this Structure

1D1V is a Single protein structure of sequence from Bos taurus with , , , , , and as ligands. Active as Nitric-oxide synthase, with EC number 1.14.13.39 Full crystallographic information is available from OCA.

Reference

Implications for isoform-selective inhibitor design derived from the binding mode of bulky isothioureas to the heme domain of endothelial nitric-oxide synthase., Raman CS, Li H, Martasek P, Babu BR, Griffith OW, Masters BS, Poulos TL, J Biol Chem. 2001 Jul 13;276(28):26486-91. Epub 2001 Apr 30. PMID:11331290

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