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PDBsum entry 1u3v
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Oxidoreductase
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PDB id
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1u3v
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References listed in PDB file
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Key reference
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Title
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Structure of three class I human alcohol dehydrogenases complexed with isoenzyme specific formamide inhibitors.
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Authors
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B.J.Gibbons,
T.D.Hurley.
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Ref.
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Biochemistry, 2004,
43,
12555-12562.
[DOI no: ]
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PubMed id
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Abstract
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Formamides are aldehyde analogues that have demonstrated potent and selective
inhibition of human alcohol dehydrogenase isoenzymes. The alphaalpha,
beta(1)beta(1), gamma(2)gamma(2), and sigmasigma isoforms have all been found to
be strongly inhibited by substituted formamides. In this paper, the structure of
the alphaalpha isoform of human alcohol dehydrogenase complexed with
N-cyclopentyl-N-cyclobutylformamide was determined by X-ray crystallography to
2.5 A resolution, the beta(1)beta(1) isoform of human alcohol dehydrogenase
complexed with N-benzylformamide and with N-heptylformamide was determined to
1.6 and 1.65 A resolution, respectively, and the structure of the
gamma(2)gamma(2) isoform complexed with N-1-methylheptylformamide was determined
to 1.45 A resolution. These structures provide the first substrate-level view of
the local structural differences that give rise to the individual substrate
preferences shown by these highly related isoenzymes. Consistent with previous
work, the carbonyl oxygen of the inhibitors interacts directly with the
catalytic zinc and the hydroxyl group of Thr48 (Ser48 for gamma(2)gamma(2)) of
the enzyme. The benzene ring of N-benzylformamide and the carbon chains of
N-heptylformamide and N-1-methylheptylformamide interact with the sides of the
hydrophobic substrate pocket whose size and shape is dictated by residue
exchanges between the beta(1)beta(1) and gamma(2)gamma(2) isoenzymes. In
particular, the exchange of Ser for Thr at position 48 and the exchange of Val
for Leu at position 141 in the gamma(2)gamma(2) isoenzyme create an environment
with stereoselectivity for the R-enantiomer of the branched
N-1-methylheptylformamide inhibitor in this isoenzyme. The primary feature of
the alphaalpha isoform is the Ala for Phe93 exchange that enlarges the active
site near the catalytic zinc and creates the specificity for the branched
N-cyclopentyl-N-cyclobutylformamide inhibitor, which shows the greatest
selectivity for this unique isoenzyme of any of the formamide inhibitors.
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