CRYSTALLOGRAPHIC STUDIES OF 2 ALCOHOL DEHYDROGENASE-BOUND ANALOGS OF THIAZOLE-4-CARBOXAMIDE ADENINE-DINUCLEOTIDE (TAD), THE ACTIVE ANABOLITE OF THE ANTITUMOR AGENT TIAZOFURIN

被引:65
作者
LI, H
HALLOWS, WH
PUNZI, JS
MARQUEZ, VE
CARRELL, HL
PANKIEWICZ, KW
WATANABE, KA
GOLDSTEIN, BM
机构
[1] UNIV ROCHESTER, SCH MED & DENT, DEPT BIOPHYS, ROCHESTER, NY 14642 USA
[2] NCI, DIV CANC TREATMENT, DEV THERAPEUT PROGRAM, MED CHEM LAB, BETHESDA, MD 20892 USA
[3] FOX CHASE CANC CTR, INST CANC RES, PHILADELPHIA, PA 19111 USA
[4] MEM SLOAN KETTERING CANC CTR, NEW YORK, NY 10021 USA
关键词
D O I
10.1021/bi00167a004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 angstrom, 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 angstrom 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 coenyzme 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 angstrom. 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.
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页码:23 / 32
页数:10
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