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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: Journal of Structural Biology; v. 215, n. 2, p. 10-pg., 2023-03-23.

Resumo

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)

• Processo FAPESP: 16/18721-4 - Bases estruturais do controle da elongação e da divisão celular em Mycobacterium tuberculosis e identificação de novos hits a fármacos baseado em triagem de fragmentos
• Beneficiário: Catharina dos Santos Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 19/17037-0 - Identificação de compostos que interagem com a MurE de Mycobacterium tuberculosis através da triagem de fragmentos
• Beneficiário: Nicolas de Oliveira Rossini
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 20/03850-9 - Parede celular micobacteriana: estudo estrutural e estratégias de inibição de enzimas relacionadas com sua biossíntese e regulação
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular