The crystal structure of Mycobacterium thermoresistibile MurE ligase reveals the binding mode of the substrate m-diaminopimelate

Author(s)

Rossini, Nicolas de Oliveira ; Silva, Catharina ; Dias, Marcio Vinicius Bertacine

• Document type: Journal article
• Source: Journal of Structural Biology; v. 215, n. 2, p. 10-pg., 2023-03-23.

Abstract

The cytoplasmatic biosynthesis of the stem peptide from the peptidoglycan in bacteria involves six steps, which have the role of three ATP-dependent Mur ligases that incorporate three consecutive amino acids to a substrate precursor. MurE is the last Mur ligase to incorporate a free amino acid. Although the structure of MurE from Mycobacterium tuberculosis (MtbMurE) was determined at 3.0 angstrom, the binding mode of meso-Diaminopimelate (m -DAP) and the effect of substrate absence is unknown. Herein, we show the structure of MurE from M. thermoresistibile (MthMurE) in complex with ADP and m-DAP at 1.4 angstrom resolution. The analysis of the structure indicates key conformational changes that the substrate UDP-MurNAc-L-Ala-D-Glu (UAG) and the free amino acid m-DAP cause on the MthMurE conformation. We observed several movements of domains or loop regions that displace their position in order to perform enzymatic catalysis. Since MthMurE has a high similarity to MtbMurE, this enzyme could also guide strategies for structure-based antimicrobial discovery to fight against tuberculosis or other mycobacterial infections. (AU)

• FAPESP's process: 16/18721-4 - Structural basis of the elongation and cell division control in Mycobacterium tuberculosis and identification of new drug hits based in fragment trials
• Grantee: Catharina dos Santos Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/17037-0 - Discovery of compounds that interact with MurE from Mycobacterium tuberculosis using fragment screening
• Grantee: Nicolas de Oliveira Rossini
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 20/03850-9 - Mycobacterium cell wall: structural studies and inhibition strategies for enzymes involved in the biosynthesis and regulation
• Grantee: Marcio Vinicius Bertacine Dias
• Support Opportunities: Regular Research Grants