1p6m
From Proteopedia
(New page: 200px<br /><applet load="1p6m" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p6m, resolution 2.27Å" /> '''Bovine endothelial N...) |
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| - | [[Image:1p6m.jpg|left|200px]]<br /><applet load="1p6m" size=" | + | [[Image:1p6m.jpg|left|200px]]<br /><applet load="1p6m" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1p6m, resolution 2.27Å" /> | caption="1p6m, resolution 2.27Å" /> | ||
'''Bovine endothelial NOS heme domain with (4S)-N-(4-amino-5-[aminoethyl]aminopentyl)-N'-nitroguanidine bound'''<br /> | '''Bovine endothelial NOS heme domain with (4S)-N-(4-amino-5-[aminoethyl]aminopentyl)-N'-nitroguanidine bound'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Three nitric oxide synthase (NOS) isoforms, eNOS, nNOS and iNOS, generate | + | Three nitric oxide synthase (NOS) isoforms, eNOS, nNOS and iNOS, generate nitric oxide (NO) crucial to the cardiovascular, nervous and host defense systems, respectively. Development of isoform-selective NOS inhibitors is of considerable therapeutic importance. Crystal structures of nNOS-selective dipeptide inhibitors in complex with both nNOS and eNOS were solved and the inhibitors were found to adopt a curled conformation in nNOS but an extended conformation in eNOS. We hypothesized that a single-residue difference in the active site, Asp597 (nNOS) versus Asn368 (eNOS), is responsible for the favored binding in nNOS. In the D597N nNOS mutant crystal structure, a bound inhibitor switches to the extended conformation and its inhibition of nNOS decreases >200-fold. Therefore, a single-residue difference is responsible for more than two orders of magnitude selectivity in inhibition of nNOS over eNOS by L-N(omega)-nitroarginine-containing dipeptide inhibitors. |
==About this Structure== | ==About this Structure== | ||
| - | 1P6M 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 CAC, ACT, ZN, HEM, H4B, DP3 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:// | + | 1P6M 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=CAC:'>CAC</scene>, <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=DP3:'>DP3</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=1P6M OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Nitric-oxide synthase]] | [[Category: Nitric-oxide synthase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Flinspach, M | + | [[Category: Flinspach, M L.]] |
| - | [[Category: Gomez-Vidal, J | + | [[Category: Gomez-Vidal, J A.]] |
| - | [[Category: Hah, J | + | [[Category: Hah, J M.]] |
[[Category: Huang, H.]] | [[Category: Huang, H.]] | ||
[[Category: Jamal, J.]] | [[Category: Jamal, J.]] | ||
[[Category: Li, H.]] | [[Category: Li, H.]] | ||
| - | [[Category: Litzinger, E | + | [[Category: Litzinger, E A.]] |
| - | [[Category: Poulos, T | + | [[Category: Poulos, T L.]] |
| - | [[Category: Silverman, R | + | [[Category: Silverman, R B.]] |
[[Category: Yang, W.]] | [[Category: Yang, W.]] | ||
[[Category: ACT]] | [[Category: ACT]] | ||
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[[Category: oxidoreductase]] | [[Category: oxidoreductase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:25:40 2008'' |
Revision as of 12:25, 21 February 2008
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Bovine endothelial NOS heme domain with (4S)-N-(4-amino-5-[aminoethyl]aminopentyl)-N'-nitroguanidine bound
Overview
Three nitric oxide synthase (NOS) isoforms, eNOS, nNOS and iNOS, generate nitric oxide (NO) crucial to the cardiovascular, nervous and host defense systems, respectively. Development of isoform-selective NOS inhibitors is of considerable therapeutic importance. Crystal structures of nNOS-selective dipeptide inhibitors in complex with both nNOS and eNOS were solved and the inhibitors were found to adopt a curled conformation in nNOS but an extended conformation in eNOS. We hypothesized that a single-residue difference in the active site, Asp597 (nNOS) versus Asn368 (eNOS), is responsible for the favored binding in nNOS. In the D597N nNOS mutant crystal structure, a bound inhibitor switches to the extended conformation and its inhibition of nNOS decreases >200-fold. Therefore, a single-residue difference is responsible for more than two orders of magnitude selectivity in inhibition of nNOS over eNOS by L-N(omega)-nitroarginine-containing dipeptide inhibitors.
About this Structure
1P6M 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
Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase., Flinspach ML, Li H, Jamal J, Yang W, Huang H, Hah JM, Gomez-Vidal JA, Litzinger EA, Silverman RB, Poulos TL, Nat Struct Mol Biol. 2004 Jan;11(1):54-9. Epub 2003 Dec 29. PMID:14718923
Page seeded by OCA on Thu Feb 21 14:25:40 2008
Categories: Bos taurus | Nitric-oxide synthase | Single protein | Flinspach, M L. | Gomez-Vidal, J A. | Hah, J M. | Huang, H. | Jamal, J. | Li, H. | Litzinger, E A. | Poulos, T L. | Silverman, R B. | Yang, W. | ACT | CAC | DP3 | GOL | H4B | HEM | ZN | Heme-enzyme | Nitric oxide synthase | Oxidoreductase
