1frb
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FR-1 PROTEIN/NADPH/ZOPOLRESTAT COMPLEX
OverviewOverview
Murine FR-1 is a protein that is induced by fibroblast growth factor-1, and, therefore, may play a role in the regulation of the cell cycle., Sequence comparison indicates that it is a member of the NADPH-dependent, aldo-keto reductase family. It bears 70% identity to human aldose, reductase, an enzyme implicated in diabetic complications and a target for, drug design. We have determined the 1.7 A resolution structure of the FR-1, in a ternary complex with NADPH and zopolrestat, a potent aldose reductase, inhibitor. FR-1 folds into a (beta/alpha)8 barrel with an active site, characterized by a preponderance of hydrophobic residues residing in a, deep oblong cavity at the C-terminal end of the beta-barrel. The, nicotinamide moiety of the coenzyme sits in the base of the cavity., Zopolrestat occupies the active site cavity and makes numerous contacts, with several hydrophobic residues. The FR-1 ternary complex structure, indicates that it uses the same general catalytic mechanism as aldose, reductase and other members of the family whose structures have been, determined. The protein exhibits reductase activity with DL-glyceraldehyde, as a substrate and is strongly inhibited by zopolrestat. When compared, with the structure of a similar ternary complex of aldose reductase, the, binding site retains many of the interactions with the coenzyme and, inhibitor from the conserved residues. Some differences in sequence, however, create a larger binding site that contains six more water, molecules than in the aldose reductase ternary complex structure.(ABSTRACT, TRUNCATED AT 250 WORDS)
About this StructureAbout this Structure
1FRB is a Single protein structure of sequence from Mus musculus with NAP and ZST as ligands. Full crystallographic information is available from OCA.
ReferenceReference
1.7 A structure of FR-1, a fibroblast growth factor-induced member of the aldo-keto reductase family, complexed with coenzyme and inhibitor., Wilson DK, Nakano T, Petrash JM, Quiocho FA, Biochemistry. 1995 Nov 7;34(44):14323-30. PMID:7578036
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