Greasley S E, Horton P, Ramcharan J, Beardsley G P, Benkovic S J, Wilson I A
Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nat Struct Biol. 2001 May;8(5):402-6. doi: 10.1038/87555.
ATIC, the product of the purH gene, is a 64 kDa bifunctional enzyme that possesses the final two activities in de novo purine biosynthesis, AICAR transformylase and IMP cyclohydrolase. The crystal structure of avian ATIC has been determined to 1.75 A resolution by the MAD method using a Se-methionine modified enzyme. ATIC forms an intertwined dimer with an extensive interface of approximately 5,000 A(2) per monomer. Each monomer is composed of two novel, separate functional domains. The N-terminal domain (up to residue 199) is responsible for the IMPCH activity, whereas the AICAR Tfase activity resides in the C-terminal domain (200-593). The active sites of the IMPCH and AICAR Tfase domains are approximately 50 A apart, with no structural evidence of a tunnel connecting the two active sites. The crystal structure of ATIC provides a framework to probe both catalytic mechanisms and to design specific inhibitors for use in cancer chemotherapy and inflammation.
ATIC是purH基因的产物，是一种64 kDa的双功能酶，在嘌呤从头生物合成中具有最后的两种活性，即氨基咪唑甲酰胺核苷酸（AICAR）转甲酰基酶和肌苷酸（IMP）环水解酶。利用硒代甲硫氨酸修饰的酶，通过多波长反常散射（MAD）方法，已将禽源ATIC的晶体结构解析到1.75 Å的分辨率。ATIC形成一个相互缠绕的二聚体，每个单体具有约5000 Ų的广泛界面。每个单体由两个新的、独立的功能结构域组成。N端结构域（至第199位残基）负责IMPCH活性，而AICAR转甲酰基酶活性位于C端结构域（200 - 593）。IMPCH和AICAR转甲酰基酶结构域的活性位点相距约50 Å，没有结构证据表明两个活性位点之间存在通道。ATIC的晶体结构为探究两种催化机制以及设计用于癌症化疗和炎症治疗的特异性抑制剂提供了一个框架。
