1mar: Difference between revisions

Revision as of 14:53, 21 February 2008

REFINED 1.8 ANGSTROMS STRUCTURE OF HUMAN ALDOSE REDUCTASE COMPLEXED WITH THE POTENT INHIBITOR ZOPOLRESTAT

OverviewOverview

As the action of aldose reductase (EC 1.1.1.21) is believed to be linked to the pathogenesis of diabetic complications affecting the nervous, renal, and visual systems, the development of therapeutic agents has attracted intense effort. We report the refined 1.8 A x-ray structure of the human holoenzyme complexed with zopolrestat, one of the most potent noncompetitive inhibitors. The zopolrestat fits snugly in the hydrophobic active site pocket and induces a hinge-flap motion of two peptide segments that closes the pocket. Excellent complementarity and affinity are achieved on inhibitor binding by the formation of 110 contacts (< or = 4 A) with 15 residues (10 hydrophobic), 13 with the NADPH coenzyme and 9 with four water molecules. The structure is key to understanding the mode of action of this class of inhibitors and for rational design of better therapeutics.

About this StructureAbout this Structure

1MAR is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Aldehyde reductase, with EC number 1.1.1.21 Full crystallographic information is available from OCA.

ReferenceReference

Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat., Wilson DK, Tarle I, Petrash JM, Quiocho FA, Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9847-51. PMID:8234324

Page seeded by OCA on Thu Feb 21 13:53:18 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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-[[Image:1mar.gif|left|200px]]<br />
+[[Image:1mar.gif|left|200px]]<br /><applet load="1mar" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1mar" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1mar, resolution 1.8&Aring;" />
 '''REFINED 1.8 ANGSTROMS STRUCTURE OF HUMAN ALDOSE REDUCTASE COMPLEXED WITH THE POTENT INHIBITOR ZOPOLRESTAT'''<br />
 ==Overview==
-As the action of aldose reductase (EC 1.1.1.21) is believed to be linked, to the pathogenesis of diabetic complications affecting the nervous, renal, and visual systems, the development of therapeutic agents has, attracted intense effort. We report the refined 1.8 A x-ray structure of, the human holoenzyme complexed with zopolrestat, one of the most potent, noncompetitive inhibitors. The zopolrestat fits snugly in the hydrophobic, active site pocket and induces a hinge-flap motion of two peptide segments, that closes the pocket. Excellent complementarity and affinity are, achieved on inhibitor binding by the formation of 110 contacts (&lt; or = 4, A) with 15 residues (10 hydrophobic), 13 with the NADPH coenzyme and 9, with four water molecules. The structure is key to understanding the mode, of action of this class of inhibitors and for rational design of better, therapeutics.
+As the action of aldose reductase (EC 1.1.1.21) is believed to be linked to the pathogenesis of diabetic complications affecting the nervous, renal, and visual systems, the development of therapeutic agents has attracted intense effort. We report the refined 1.8 A x-ray structure of the human holoenzyme complexed with zopolrestat, one of the most potent noncompetitive inhibitors. The zopolrestat fits snugly in the hydrophobic active site pocket and induces a hinge-flap motion of two peptide segments that closes the pocket. Excellent complementarity and affinity are achieved on inhibitor binding by the formation of 110 contacts (&lt; or = 4 A) with 15 residues (10 hydrophobic), 13 with the NADPH coenzyme and 9 with four water molecules. The structure is key to understanding the mode of action of this class of inhibitors and for rational design of better therapeutics.
 ==About this Structure==
-MAR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAP and ZST as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1MAR OCA].
+MAR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=ZST:'>ZST</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MAR OCA].
 ==Reference==
@@ Line 15: / Line 14: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Quiocho, F.A.]]
+[[Category: Quiocho, F A.]]
-[[Category: Wilson, D.K.]]
+[[Category: Wilson, D K.]]
 [[Category: NAP]]
 [[Category: ZST]]
 [[Category: oxidoreductase(nadp)]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:09:42 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:53:18 2008''