title: Structural basis of allele variation of human thiopurine-S-methyltransferase.
abstract: Human thiopurine S-methyltransferase (TPMT) exhibits considerable person-to-person variation in activity to thiopurine drugs. We have produced an N-terminal truncation of human TPMT protein, crystallized the protein in complex with the methyl donor product S-adenosyl-L-homocysteine, and determined the atomic structure to the resolution of 1.58 and 1.89 A, respectively, for the seleno-methionine incorporated and wild type proteins. The structure of TPMT indicates that the naturally occurring amino acid polymorphisms scatter throughout the structure, and that the amino acids whose alteration have the most influence on function are those that form intra-molecular stabilizing interactions (mainly van der Waals contacts). Furthermore, we have produced four TPMT mutant proteins containing variant alleles of TPMT*2, *3A, *3B, and *3C and examined the structure-function relationship of the mutant proteins based on their expression and solubility in bacteria and their thermostability profile.
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: John R
authors.initials: JR
authors.lastname: Horton
authors.forename: Kevin
authors.initials: K
authors.lastname: Battaile
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Fernando
authors.initials: F
authors.lastname: Martin
authors.forename: Hong
authors.initials: H
authors.lastname: Zeng
authors.forename: Peter
authors.initials: P
authors.lastname: Loppnau
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Alexey
authors.initials: A
authors.lastname: Bochkarev
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D011110:Polymorphism, Genetic; D012435:S-Adenosylhomocysteine / Q000378:metabolism
chemical_list: D012435:S-Adenosylhomocysteine; D008780:Methyltransferases; C022745:thiopurine methyltransferase