THE CRYSTAL STRUCTURE OF CLASS 3 ALDEHYDE DEHYDROGENASE: IMPLICATIONS TO THE CLASS 1 AND 2 ENZYMES. Zhi-Jie Liu1, Julie Sun2, John Rose1, David Hsiao2, Wen-Rui Chang1, Yong-Je Chung2, Ingrid Kuo3, John Hempel3 Ronald Lindhal4 and Bi-Cheng Wang1, 1Dept. of Biochemistry and Molecular Biology, Univ. of Georgia, Athens, GA 30602, U.S.A., Dept. of Crystallography, 2Univ. of Pittsburgh, Pittsburgh, PA 15260, U.S.A., 3Dept. of Molecular Genetics and Biochemistry, Univ. of Pittsburgh, Pittsburgh, PA 15219, U.S.A. and 4Dept. of Biochemistry and Molecular Biology, Univ. of South Dakota, Vermillion, SD 57069, U.S.A.
The first structure of an aldehyde dehydrogenase (class 3, 452 residues) from rat liver has been determined at 2.6Å resolution using SIRAS data and solvent flattening. There are two molecules in the crystallographic asymmetric unit which self-associate to form a homodimer. The structure shows two open [[alpha]]/[[beta]] domains. The NAD binding domain (residues 1-200) shows a variant Rossmann fold with the glycine-rich segment at the end of [[beta]]-strand 4 instead of at the end of [[beta]]-strand 1 found in comparable enzymes. The transition to the catalytic domain is punctuated by a highly conserved Gly-Gly segment, residues 211-212. The catalytic domain (residues 201-400) bears an intriguing resemblance to the catalytic domain of dihydrofolate reductase. The apparent aldehyde binding site contains the strictly conserved catalytic Cys243 and the highly conserved Glu209. Another interesting feature of the structure is a 55 residue segment at C-terminus which extends back from the catalytic domain over the co-enzyme binding domain with the final 30 residues completing of the catalytic domain of the related ALDH molecule in the homodimer. Details of the structure and its implications to the Class 1 and 2 structures will be presented.
Work supported by a grant AA06985 from the National Institute of Alcohol Abuse and Alcoholism, and resources from the Pittsburgh Supercomputing Center.