6IYV

Crystal sturucture of L,D-transpeptidase LdtMt2 from Mycobacterium tuberculosis in complex with ertapenem adduct

Summary for 6IYV

• Entry DOI: 10.2210/pdb6iyv/pdb
• Related: 3VYO 3VYP
• Descriptor: L,D-transpeptidase 2, (2S,3R,4S)-4-({(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl}sulfanyl)-2-[(1S,2R)-1-formyl-2-hydroxypropyl]-3-methyl-3,4-dihydro-2H-pyrrole-5-carboxylic acid, GLYCEROL, ... (7 entities in total)
• Functional Keywords: ld-transpeptidase, peptidoglycan synthesis enzyme, beta-lactam binding, transferase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 2
• Total formula weight: 61411.83

Authors

Zhao, F.,Li, D.F.,Wang, D.C. (deposition date: 2018-12-17, release date: 2019-02-27, Last modification date: 2024-10-30)

Primary citation

Zhao, F.,Hou, Y.J.,Zhang, Y.,Wang, D.C.,Li, D.F.
The 1-beta-methyl group confers a lower affinity of l,d-transpeptidase LdtMt2for ertapenem than for imipenem.
Biochem. Biophys. Res. Commun., 510:254-260, 2019

PubMed Abstract: L,D-transpeptidases, widely distributed in bacteria and even in the difficult-to-treat ESKAPE pathogens, can confer antibacterial resistance against the traditional β-lactam antibiotics through bypass of the 4 → 3 transpeptide linkage. Ldt, a l,d-transpeptidase in Mycobacteria tuberculosis, is essential for bacterial virulence and is considered as a potential anti-tuberculosis target inhibited by carbapenems. Diverse interaction modes between carbapenems and Ldt have been reported, there are only limited evidences to validate those interaction modes. Herein, we identified the stable binding states of two carbapenems, imipenem and ertapenem, via crystallographic and biochemical studies, discovered that they adopt similar binding conformations. We further demonstrate the absence of the 1-β-methyl group in imipenem and the presence of both Y308 and Y318 residues in Ldt synergistically resulted in one order of magnitude higher affinity for imipenem than ertapenem. Our study provides a structural basis for the rational drug design and evolvement of novel carbapenems against bacterial L,D-transpeptidases.

PubMed: 30686533
DOI: 10.1016/j.bbrc.2019.01.082

Experimental method

X-RAY DIFFRACTION (1.5 Å)