PDBsum entry 1u3v

Oxidoreductase

PDB id: 1u3v

Contents

Protein chain

374 a.a. *

Ligands

NAD ×2

HPL ×2

PO4

Metals

_ZN ×4

Waters ×1052

* Residue conservation analysis

PDB id:

1u3v

Name:

Oxidoreductase

Title:

Crystal structure of human alcohol dehydrogenase beta-1-beta-1 isoform complexed with n-heptylformamide determined to 1.65 angstrom resolution

Structure:

Alcohol dehydrogenase beta chain. Chain: a, b. Synonym: alcohol dehydrogenase beta-1-beta-1 isoform. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: adh1b. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

1.65Å R-factor: 0.164 R-free: 0.185

Authors:

B.J.Gibbons,T.D.Hurley

Key ref:

B.J.Gibbons and T.D.Hurley (2004). Structure of three class I human alcohol dehydrogenases complexed with isoenzyme specific formamide inhibitors. Biochemistry, 43, 12555-12562. PubMed id: 15449945 DOI: 10.1021/bi0489107

Date:

23-Jul-04 Release date: 26-Oct-04

Protein chains

P00325  (ADH1B_HUMAN) -  All-trans-retinol dehydrogenase [NAD(+)] ADH1B from Homo sapiens

Seq: 375 a.a.

Struc: 374 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.1.1.1.105 - all-trans-retinol dehydrogenase (NAD(+)).
• Reaction: all-trans-retinol--[retinol-binding protein] + NAD⁺ = all-trans- retinal--[retinol-binding protein] + NADH + H⁺

all-trans-retinol--[retinol-binding protein] + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = all-trans- retinal--[retinol-binding protein] + NADH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/bi0489107

Biochemistry 43:12555-12562 (2004)

PubMed id: 15449945

Structure of three class I human alcohol dehydrogenases complexed with isoenzyme specific formamide inhibitors.

B.J.Gibbons, T.D.Hurley.

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.