1U3U

Crystal Structure of Human Alcohol Dehydrogenase Beta-1-Beta-1 Isoform Complexed with N-Benzylformamide Determined to 1.6 Angstrom Resolution

Summary for 1U3U

• Entry DOI: 10.2210/pdb1u3u/pdb
• Related: 1HSZ 1U3T 1U3V 1U3W
• Descriptor: Alcohol dehydrogenase beta chain, ZINC ION, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (6 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00325
• Total number of polymer chains: 2
• Total formula weight: 81500.34

Authors

Gibbons, B.J.,Hurley, T.D. (deposition date: 2004-07-23, release date: 2004-10-26, Last modification date: 2023-10-25)

Primary citation

Gibbons, B.J.,Hurley, T.D.
Structure of three class I human alcohol dehydrogenases complexed with isoenzyme specific formamide inhibitors
Biochemistry, 43:12555-12562, 2004

PubMed Abstract: 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.

PubMed: 15449945
DOI: 10.1021/bi0489107

Experimental method

X-RAY DIFFRACTION (1.6 Å)