PDBsum entry: 1d1s

Oxidoreductase

PDB id: 1d1s

Contents

Protein chains

373 a.a. *

Ligands

ACT ×13

CAC ×5

NAD ×4

Metals

_ZN ×19

Waters ×408

* Residue conservation analysis

PDB id:

1d1s

Name:

Oxidoreductase

Title:

Wild-type human sigma (class iv) alcohol dehydrogenase

Structure:

Alcohol dehydrogenase class iv sigma chain. Chain: a, b, c, d. Synonym: retinol dehydrogenase, gastric alcohol dehydrogena engineered: yes

Source:

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

Biol. unit:

Dimer (from PQS)

Resolution:

2.50Å R-factor: 0.217 R-free: 0.268

Authors:

P.T.Xie,T.D.Hurley

Key ref:

P.T.Xie and T.D.Hurley (1999). Methionine-141 directly influences the binding of 4-methylpyrazole in human sigma sigma alcohol dehydrogenase. Protein Sci, 8, 2639-2644. PubMed id: 10631979 Ref: Full text

Date:

21-Sep-99 Release date: 29-Sep-99

Protein chains

P40394  (ADH7_HUMAN) -  Alcohol dehydrogenase class 4 mu/sigma chain

Seq: 386 a.a.

Struc: 373 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.1 - Alcohol dehydrogenase.
• Reaction: An alcohol + NAD⁺ = an aldehyde or ketone + NADH

alcohol + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = aldehyde or ketone + NADH

• Cofactor: Zinc or iron

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

 Gene Ontology (GO) functional annotation 

• Cellular component: soluble fraction (3 terms)
• Biological process: oxidation-reduction process (8 terms)
• Biochemical function: nucleotide binding (11 terms)

reference

Full text	Protein Sci 8:2639-2644 (1999)
PubMed id: 10631979

Methionine-141 directly influences the binding of 4-methylpyrazole in human sigma sigma alcohol dehydrogenase.

P.T.Xie, T.D.Hurley.

ABSTRACT

Pyrazole and its 4-alkyl substituted derivatives are potent inhibitors for many alcohol dehydrogenases. However, the human sigma sigma isoenzyme exhibits a 580-fold lower affinity for 4-methylpyrazole than does the human beta1beta1 isoenzyme, with which it shares 69% sequence identity. In this study, structural and kinetic studies were utilized in an effort to identify key structural features that affect the binding of 4-methylpyrazole in human alcohol dehydrogenase isoenzymes. We have extended the resolution of the human sigma sigma alcohol dehydrogenase (ADH) isoenzyme to 2.5 A resolution. Comparison of this structure to the human beta1beta1 isoenzyme structure indicated that the side-chain position for Met141 in sigma sigma ADH might interfere with 4-methylpyrazole binding. Mutation of Met141 in sigma sigma ADH to Leu (sigma141L) lowers the Ki for 4-methylpyrazole from 350 to 10 microM, while having a much smaller effect on the Ki for pyrazole. Thus, the mutagenesis results show that the residue at position 141, which lines the substrate-binding pocket at a position close to the methyl group of 4-methylpyrazole, directly affects the binding of the inhibitor. To rule out nonspecific structural changes due to the mutation, the X-ray structure of the sigma141L mutant enzyme was determined to 2.4 A resolution. The three-dimensional structure of the mutant enzyme is identical to the wild-type enzyme, with the exception of the residue at position 141. Thus, the differences in 4-methylpyrazole binding between the mutant and wild-type sigma sigma ADH isoenzymes can be completely ascribed to the local changes in the topology of the substrate binding site, and provides an explanation for the class-specific differences in 4-methylpyrazole binding to the human ADH isoenzymes.