1rs6
From Proteopedia
(New page: 200px<br /><applet load="1rs6" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rs6, resolution 1.95Å" /> '''Rat neuronal NOS hem...) |
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| - | [[Image:1rs6.gif|left|200px]]<br /><applet load="1rs6" size=" | + | [[Image:1rs6.gif|left|200px]]<br /><applet load="1rs6" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1rs6, resolution 1.95Å" /> | caption="1rs6, resolution 1.95Å" /> | ||
'''Rat neuronal NOS heme domain with D-lysine-D-nitroarginine amide bound'''<br /> | '''Rat neuronal NOS heme domain with D-lysine-D-nitroarginine amide bound'''<br /> | ||
==Overview== | ==Overview== | ||
| - | In a continuing effort to unravel the structural basis for | + | In a continuing effort to unravel the structural basis for isoform-selective inhibition of nitric oxide synthase (NOS) by various inhibitors, we have determined the crystal structures of the nNOS and eNOS heme domain bound with two D-nitroarginine-containing dipeptide inhibitors, D-Lys-D-Arg(NO)2-NH(2) and D-Phe-D-Arg(NO)2-NH(2). These two dipeptide inhibitors exhibit similar binding modes in the two constitutive NOS isozymes, which is consistent with the similar binding affinities for the two isoforms as determined by K(i) measurements. The D-nitroarginine-containing dipeptide inhibitors are not distinguished by the amino acid difference between nNOS and eNOS (Asp 597 and Asn 368, respectively) which is key in controlling isoform selection for nNOS over eNOS observed for the L-nitroarginine-containing dipeptide inhibitors reported previously [Flinspach, M., et al. (2004) Nat. Struct. Mol. Biol. 11, 54-59]. The lack of a free alpha-amino group on the D-nitroarginine moiety makes the dipeptide inhibitor steer away from the amino acid binding pocket near the active site. This allows the inhibitor to extend into the solvent-accessible channel farther away from the active site, which enables the inhibitors to explore new isoform-specific enzyme-inhibitor interactions. This might be the structural basis for why these D-nitroarginine-containing inhibitors are selective for nNOS (or eNOS) over iNOS. |
==About this Structure== | ==About this Structure== | ||
| - | 1RS6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with MAN, ACT, ZN, HEM, H4B and DP2 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:// | + | 1RS6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=MAN:'>MAN</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> and <scene name='pdbligand=DP2:'>DP2</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=1RS6 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Jamal, J.]] | [[Category: Jamal, J.]] | ||
[[Category: Li, H.]] | [[Category: Li, H.]] | ||
| - | [[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 14:53:58 2008'' |
Revision as of 12:53, 21 February 2008
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Rat neuronal NOS heme domain with D-lysine-D-nitroarginine amide bound
Overview
In a continuing effort to unravel the structural basis for isoform-selective inhibition of nitric oxide synthase (NOS) by various inhibitors, we have determined the crystal structures of the nNOS and eNOS heme domain bound with two D-nitroarginine-containing dipeptide inhibitors, D-Lys-D-Arg(NO)2-NH(2) and D-Phe-D-Arg(NO)2-NH(2). These two dipeptide inhibitors exhibit similar binding modes in the two constitutive NOS isozymes, which is consistent with the similar binding affinities for the two isoforms as determined by K(i) measurements. The D-nitroarginine-containing dipeptide inhibitors are not distinguished by the amino acid difference between nNOS and eNOS (Asp 597 and Asn 368, respectively) which is key in controlling isoform selection for nNOS over eNOS observed for the L-nitroarginine-containing dipeptide inhibitors reported previously [Flinspach, M., et al. (2004) Nat. Struct. Mol. Biol. 11, 54-59]. The lack of a free alpha-amino group on the D-nitroarginine moiety makes the dipeptide inhibitor steer away from the amino acid binding pocket near the active site. This allows the inhibitor to extend into the solvent-accessible channel farther away from the active site, which enables the inhibitors to explore new isoform-specific enzyme-inhibitor interactions. This might be the structural basis for why these D-nitroarginine-containing inhibitors are selective for nNOS (or eNOS) over iNOS.
About this Structure
1RS6 is a Single protein structure of sequence from Rattus norvegicus with , , , , and as ligands. Active as Nitric-oxide synthase, with EC number 1.14.13.39 Full crystallographic information is available from OCA.
Reference
Structures of the neuronal and endothelial nitric oxide synthase heme domain with D-nitroarginine-containing dipeptide inhibitors bound., Flinspach M, Li H, Jamal J, Yang W, Huang H, Silverman RB, Poulos TL, Biochemistry. 2004 May 11;43(18):5181-7. PMID:15122883
Page seeded by OCA on Thu Feb 21 14:53:58 2008
Categories: Nitric-oxide synthase | Rattus norvegicus | Single protein | Flinspach, M. | Huang, H. | Jamal, J. | Li, H. | Poulos, T L. | Silverman, R B. | Yang, W. | ACT | DP2 | H4B | HEM | MAN | ZN | Heme-enzyme | Nitric oxide synthase | Oxidoreductase
