1adf

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spinqualitylabelsall models 1adf, resolution 2.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTALLOGRAPHIC STUDIES OF TWO ALCOHOL DEHYDROGENASE-BOUND ANALOGS OF THIAZOLE-4-CARBOXAMIDE ADENINE DINUCLEOTIDE (TAD), THE ACTIVE ANABOLITE OF THE ANTITUMOR AGENT TIAZOFURIN

Overview

Thiazole-4-carboxamide adenine dinucleotide (TAD) is the active anabolite, of the antitumor drug tiazofurin. Beta-methylene TAD (beta-TAD) is a, phosphodiesterase-resistant analogue of TAD, active in, tiazofurin-resistant cells. Beta-methylene SAD (beta-SAD) is the active, selenium derivative of beta-TAD. Both agents are analogues of the cofactor, NAD and are capable of acting as general dehydrogenase inhibitors. Crystal, structures of beta-TAD and beta-SAD bound to horse liver alcohol, dehydrogenase (LADH) are presented at 2.9 and 2.7 A, respectively. Both, complexes crystallize in the orthorhombic space group C222(1) and are, isomorphous to apo-LADH. Complexes containing beta-TAD and beta-SAD were, refined to crystallographic R values of 15% and 16%, respectively, for, reflections between 8 A and the minimum d spacing. Conformations of both, inhibitors are similar. beta-TAD and beta-SAD bind to the "open" form of, LADH in the normal cofactor-binding cleft between the coenzyme and, catalytic domains of each monomer. Binding at the adenosine end of each, inhibitor resembles that of NAD. However, the positions of the thiazole, and selenazole heterocycles are displaced away from the catalytic Zn, cation by approximately 4 A. Close intramolecular S-O and Se-O contacts, observed in the parent nucleoside analogues are maintained in both, LADH-bound beta-TAD and beta-SAD, respectively. These conformational, constraints may influence the binding specificity of the inhibitors.

About this Structure

1ADF is a Single protein structure of sequence from Equus caballus with ZN and TAD as ligands. Active as Alcohol dehydrogenase, with EC number 1.1.1.1 Full crystallographic information is available from OCA.

Reference

Crystallographic studies of two alcohol dehydrogenase-bound analogues of thiazole-4-carboxamide adenine dinucleotide (TAD), the active anabolite of the antitumor agent tiazofurin., Li H, Hallows WH, Punzi JS, Marquez VE, Carrell HL, Pankiewicz KW, Watanabe KA, Goldstein BM, Biochemistry. 1994 Jan 11;33(1):23-32. PMID:8286346

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