1ADF

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

Summary for 1ADF

• Entry DOI: 10.2210/pdb1adf/pdb
• Descriptor: ALCOHOL DEHYDROGENASE, ZINC ION, BETA-METHYLENE-THIAZOLE-4-CARBOXYAMIDE-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: oxidoreductase(nad(a)-choh(d))
• Biological source: Equus caballus (horse)
• Cellular location: Cytoplasm: P00327
• Total number of polymer chains: 1
• Total formula weight: 40651.57

Authors

Li, H.,Hallows, W.A.,Punzi, J.S.,Marquez, V.E.,Carrell, H.L.,Pankiewicz, K.W.,Watanabe, K.A.,Goldstein, B.M. (deposition date: 1993-10-18, release date: 1994-01-31, Last modification date: 2024-02-07)

Primary citation

Li, H.,Hallows, W.H.,Punzi, J.S.,Marquez, V.E.,Carrell, H.L.,Pankiewicz, K.W.,Watanabe, K.A.,Goldstein, B.M.
Crystallographic studies of two alcohol dehydrogenase-bound analogues of thiazole-4-carboxamide adenine dinucleotide (TAD), the active anabolite of the antitumor agent tiazofurin.
Biochemistry, 33:23-32, 1994

PubMed Abstract: 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.

PubMed: 8286346
DOI: 10.1021/bi00167a004

Experimental method

X-RAY DIFFRACTION (2.9 Å)