9HTY

Crystal structure of Ami2B domain of DS6A-LysA in complex with L-Ala-D-iso-Gln-L-Lys- D-Ala-D-Ala

Summary for 9HTY

• Entry DOI: 10.2210/pdb9hty/pdb
• Descriptor: N-acetylmuramoyl-L-alanine amidase, L-Ala-D-iso-Gln-L-Lys- D-Ala-D-Ala, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: peptidoglycan hydrolase, amidase, ds6a-lysa, crystal complex, hydrolase
• Biological source: Mycobacterium phage DS6A; More
• Total number of polymer chains: 6
• Total formula weight: 65685.10

Authors

Ceballos-Zuniga, F.,Perez-Dorado, I. (deposition date: 2024-12-20, release date: 2026-04-22)

Primary citation

Ceballos-Zuniga, F.,Galvez-Larrosa, L.,Munoz, I.G.,Infantes, L.,Fernandez-Carrillo, J.,Perez-Dorado, I.
Dissecting the molecular basis underlying mycobacterial cell-wall hydrolysis by the catalytic domains of D29LysA and DS6ALysA phage endolysins.
Int.J.Biol.Macromol., 334:148896-148896, 2025

PubMed Abstract: Mycobacterial infections, including tuberculosis, remain a major global health challenge, causing millions of deaths annually. Their treatment is increasingly hindered by limited therapeutic options and rising antimicrobial resistance, highlighting the urgent need for alternative strategies. Mycobacteriophage LysA endolysins are complex multi-domain peptidoglycan hydrolases emerging as potential tools to treat mycobacterial infections. However, despite the therapeutic prospects of LysAs, our understanding of their mechanism of action remains limited. This study provides a comprehensive structural-functional analysis of the catalytic domains of D29LysA and DS6ALysA endolysins (D29N4/D29GH19 and DS6AGH19/DS6AAmi2B), characterised alone and in complex with PG analogues, using protein engineering, X-ray crystallography, small-angle X-ray scattering, and in silico tools. Our results reveal precise details of the substrate-binding site and the catalytic platforms at each domain, including information about substrate-binding mode and conformational changes associated with peptidoglycan recognition and hydrolysis. Moreover, these findings also suggest a coordinated mechanism of action of both catalytic domains in DS6ALysA lysin. These insights represent a significant advance in understanding the structural basis of mycobacterial cell-wall degradation by mycobacteriophage endolysins. Information that may aid in further exploring these endolysins as therapeutic antimicrobial tools in the future.

PubMed: 41207583
DOI: 10.1016/j.ijbiomac.2025.148896

Experimental method

X-RAY DIFFRACTION (2.74 Å)