tailieunhanh - Báo cáo khoa học: Crystal structure of Thermoanaerobacter tengcongensis hypoxanthine-guanine phosphoribosyl transferase L160I mutant ) insights into inhibitor design

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a potential target for structure-based inhibitor design for the treatment of parasitic dis-eases. We created point mutants of Thermoanaerobacter tengcongensis HGPRT and tested their activities to identify side chains that were impor-tant for function. | ễFEBS Journal Crystal structure of Thermoanaerobacter tengcongensis hypoxanthine-guanine phosphoribosyl transferase L160I mutant - insights into inhibitor design Qiang Chen1 2 Delin You1 Yuhe Liang1 2 Xiaodong Su1 2 Xiaocheng Gu1 Ming Luo1 3 and Xiaofeng Zheng1 2 1 NationalLaboratory of Protein Engineering and Plant Genetic Engineering Peking University Beijing China 2 Department of Biochemistry and Molecular Biology College of Life Sciences Peking University Beijing China 3 Department of Microbiology University of Alabama at Birmingham AL USA Keywords crystal structure enzymatic activity HGPRT mutant Correspondence X. Zheng College of Life Sciences Peking University Beijing 100871 China Fax 86 10 6276 5913 Tel 86 10 6275 5712 E-mail xiaofengz@ Present address Shanghai Jiao Tong University Shanghai China Hypoxanthine-guanine phosphoribosyltransferase HGPRT is a potential target for structure-based inhibitor design for the treatment of parasitic diseases. We created point mutants of Thermoanaerobacter tengcongensis HGPRT and tested their activities to identify side chains that were important for function. Mutating residues Leu160 and Lys133 substantially diminished the activity of HGPRT confirming their importance in catalysis. All 11 HGPRT mutants were subject to crystallization screening. The crystal structure of one mutant L160I was determined at A resolution. Surprisingly the active site is occupied by a peptide from the N-terminus of a neighboring tetramer. These crystal contacts suggest an alternate strategy for structure-based inhibitor design. Received 23 April 2007 revised 17 June 2007 accepted 2 July 2007 doi Parasites cause a wide variety of human and animal diseases. These infections are routinely treated using therapeutics such as chemotherapy. A common approach for developing drug treatments against parasites is to target the biochemical and physiological differences between a pathogen and host. In living