6RYO

Bacterial membrane enzyme structure by the in meso method at 1.9 A resolution

Summary for 6RYO

• Entry DOI: 10.2210/pdb6ryo/pdb
• Descriptor: Lipoprotein signal peptidase, Globomycin, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (7 entities in total)
• Functional Keywords: in meso, lipid cubic phases, lipoprotein signal peptidase, globomycin, hydrolase
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 2
• Total formula weight: 27670.57

Authors

Huang, C.Y.,Olatunji, S.,Bailey, J.,Yu, X.,Olieric, V.,Wang, M.,Caffrey, M. (deposition date: 2019-06-11, release date: 2020-01-15, Last modification date: 2024-11-13)

Primary citation

Olatunji, S.,Yu, X.,Bailey, J.,Huang, C.Y.,Zapotoczna, M.,Bowen, K.,Remskar, M.,Muller, R.,Scanlan, E.M.,Geoghegan, J.A.,Olieric, V.,Caffrey, M.
Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin.
Nat Commun, 11:140-140, 2020

PubMed Abstract: Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.

PubMed: 31919415
DOI: 10.1038/s41467-019-13724-y

Experimental method

X-RAY DIFFRACTION (1.924 Å)