1zzr: Difference between revisions

Revision as of 17:20, 21 February 2008

Rat nNOS D597N/M336V double mutant with L-N(omega)-Nitroarginine-(4R)-amino-L-proline amide bound

OverviewOverview

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 StructureAbout this Structure

1ZZR 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.

ReferenceReference

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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OCA

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-[[Image:1zzr.gif|left|200px]]<br /><applet load="1zzr" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1zzr.gif|left|200px]]<br /><applet load="1zzr" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1zzr, resolution 2.05&Aring;" />
 '''Rat nNOS D597N/M336V double mutant with L-N(omega)-Nitroarginine-(4R)-amino-L-proline amide bound'''<br />
 ==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.
+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==
-ZZR 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 ZN, HEM, H4B, DP9, TFA 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=1ZZR OCA].
+ZZR 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=ZN:'>ZN</scene>, <scene name='pdbligand=HEM:'>HEM</scene>, <scene name='pdbligand=H4B:'>H4B</scene>, <scene name='pdbligand=DP9:'>DP9</scene>, <scene name='pdbligand=TFA:'>TFA</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=1ZZR OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Rattus norvegicus]]
 [[Category: Single protein]]
-[[Category: Flinspach, M.L.]]
+[[Category: Flinspach, M L.]]
-[[Category: Gomez-Vidal, J.A.]]
+[[Category: Gomez-Vidal, J A.]]
 [[Category: Igarashi, J.]]
 [[Category: Jamal, J.]]
 [[Category: Li, H.]]
-[[Category: Litzinger, E.A.]]
+[[Category: Litzinger, E A.]]
-[[Category: Poulos, T.L.]]
+[[Category: Poulos, T L.]]
-[[Category: Silverman, R.B.]]
+[[Category: Silverman, R B.]]
 [[Category: Yang, W.]]
 [[Category: DP9]]
@@ Line 31: / Line 31: @@
 [[Category: oxydoreductase enzyme-inhibtor complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 07:45:42 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:20:44 2008''