1zzq
From Proteopedia
(New page: 200px<br /><applet load="1zzq" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zzq, resolution 1.90Å" /> '''Rat nNOS D597N mutan...) |
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| - | [[Image:1zzq.gif|left|200px]]<br /><applet load="1zzq" size=" | + | [[Image:1zzq.gif|left|200px]]<br /><applet load="1zzq" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1zzq, resolution 1.90Å" /> | caption="1zzq, resolution 1.90Å" /> | ||
'''Rat nNOS D597N mutant with L-N(omega)-Nitroarginine-(4R)-amino-L-proline amide bound'''<br /> | '''Rat nNOS D597N mutant with L-N(omega)-Nitroarginine-(4R)-amino-L-proline amide bound'''<br /> | ||
==Overview== | ==Overview== | ||
| - | A series of L-nitroarginine-based dipeptide inhibitors are highly | + | A series of L-nitroarginine-based dipeptide inhibitors are highly selective for neuronal nitric oxide synthase (nNOS) over the endothelial isoform (eNOS). Crystal structures of these dipeptides bound to both isoforms revealed two different conformations, curled in nNOS and extended in eNOS, corresponding to higher and lower binding affinity to the two isoforms, respectively. In previous studies we found that the primary reason for selectivity is that Asp597 in nNOS, which is Asn368 in eNOS, provides greater electrostatic stabilization in the inhibitor complex. While this is the case for smaller dipeptide inhibitors, electrostatic stabilization may no longer be the sole determinant for isoform selectivity with bulkier dipeptide inhibitors. Another residue farther away from the active site, Met336 in nNOS (Val106 in eNOS), is in contact with bulkier dipeptide inhibitors. Double mutants were made to exchange the D597/M336 pair in nNOS with N368/V106 in eNOS. Here we report crystal structures and inhibition constants for bulkier dipeptide inhibitors bound to nNOS and eNOS that illustrate the important role played by residues near the entry to the active site in isoform selective inhibition. |
==About this Structure== | ==About this Structure== | ||
| - | 1ZZQ 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 ACT, ZN, MTL, HEM, H4B and DP9 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:// | + | 1ZZQ 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=ACT:'>ACT</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=MTL:'>MTL</scene>, <scene name='pdbligand=HEM:'>HEM</scene>, <scene name='pdbligand=H4B:'>H4B</scene> and <scene name='pdbligand=DP9:'>DP9</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=1ZZQ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Flinspach, M | + | [[Category: Flinspach, M L.]] |
| - | [[Category: Gomez-Vidal, J | + | [[Category: Gomez-Vidal, J A.]] |
[[Category: Igarashi, J.]] | [[Category: Igarashi, J.]] | ||
[[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: oxydoreductase enzyme-inhibitor complex]] | [[Category: oxydoreductase enzyme-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:20:43 2008'' |
Revision as of 14:20, 21 February 2008
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Rat nNOS D597N mutant with L-N(omega)-Nitroarginine-(4R)-amino-L-proline amide bound
Overview
A series of L-nitroarginine-based dipeptide inhibitors are highly selective for neuronal nitric oxide synthase (nNOS) over the endothelial isoform (eNOS). Crystal structures of these dipeptides bound to both isoforms revealed two different conformations, curled in nNOS and extended in eNOS, corresponding to higher and lower binding affinity to the two isoforms, respectively. In previous studies we found that the primary reason for selectivity is that Asp597 in nNOS, which is Asn368 in eNOS, provides greater electrostatic stabilization in the inhibitor complex. While this is the case for smaller dipeptide inhibitors, electrostatic stabilization may no longer be the sole determinant for isoform selectivity with bulkier dipeptide inhibitors. Another residue farther away from the active site, Met336 in nNOS (Val106 in eNOS), is in contact with bulkier dipeptide inhibitors. Double mutants were made to exchange the D597/M336 pair in nNOS with N368/V106 in eNOS. Here we report crystal structures and inhibition constants for bulkier dipeptide inhibitors bound to nNOS and eNOS that illustrate the important role played by residues near the entry to the active site in isoform selective inhibition.
About this Structure
1ZZQ 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
Exploring the binding conformations of bulkier dipeptide amide inhibitors in constitutive nitric oxide synthases., Li H, Flinspach ML, Igarashi J, Jamal J, Yang W, Gomez-Vidal JA, Litzinger EA, Huang H, Erdal EP, Silverman RB, Poulos TL, Biochemistry. 2005 Nov 22;44(46):15222-9. PMID:16285725
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