期刊
STRUCTURE
卷 20, 期 12, 页码 2103-2115出版社
CELL PRESS
DOI: 10.1016/j.str.2012.09.016
关键词
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资金
- U.S. Department of Energy, Office of Science [DE-AC02-06CH11357]
- U.S. Department of Energy, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- NIH [1R56AI087749, DP2OD008459]
With multidrug-resistant cases of tuberculosis increasing globally, better antibiotic drugs and novel drug targets are becoming an urgent need. Traditional beta-lactam antibiotics that inhibit D,D-transpeptidases are not effective against mycobacteria, in part because mycobacteria rely mostly on L,D-transpeptidases for biosynthesis and maintenance of their peptidoglycan layer. This reliance plays a major role in drug resistance and persistence of Mycobacterium tuberculosis (Mtb) infections. The crystal structure at 1.7 angstrom resolution of the Mtb L,D-transpeptidase Ldt(Mt2) containing a bound peptidoglycan fragment, reported here, provides information about catalytic site organization as well as substrate recognition by the enzyme. Based on our structural, kinetic, and calorimetric data, we propose a catalytic mechanism for Ldt(Mt2) in which both acyl-acceptor and acyl-donor substrates reach the catalytic site from the same, rather than different, entrances. Together, this information provides vital insights to facilitate development of drugs targeting this validated yet unexploited enzyme.
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