7NVH

Cryo-EM structure of the mycolic acid transporter MmpL3 from M. tuberculosis

Summary for 7NVH

• Entry DOI: 10.2210/pdb7nvh/pdb
• EMDB information: 12604
• Descriptor: Trehalose monomycolate exporter MmpL3, Lauryl Maltose Neopentyl Glycol (2 entities in total)
• Functional Keywords: transporter, membrane protein
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 83530.80

Authors

Adams, O.,Deme, J.C.,Parker, J.L.,Lea, S.M.,Newstead, S. (deposition date: 2021-03-15, release date: 2021-06-16, Last modification date: 2024-07-10)

Primary citation

Adams, O.,Deme, J.C.,Parker, J.L.,Fowler, P.W.,Lea, S.M.,Newstead, S.
Cryo-EM structure and resistance landscape of M. tuberculosis MmpL3: An emergent therapeutic target.
Structure, 29:1182-1191.e4, 2021

PubMed Abstract: Tuberculosis (TB) is the leading cause of death from a single infectious agent and in 2019 an estimated 10 million people worldwide contracted the disease. Although treatments for TB exist, continual emergence of drug-resistant variants necessitates urgent development of novel antituberculars. An important new target is the lipid transporter MmpL3, which is required for construction of the unique cell envelope that shields Mycobacterium tuberculosis (Mtb) from the immune system. However, a structural understanding of the mutations in Mtb MmpL3 that confer resistance to the many preclinical leads is lacking, hampering efforts to circumvent resistance mechanisms. Here, we present the cryoelectron microscopy structure of Mtb MmpL3 and use it to comprehensively analyze the mutational landscape of drug resistance. Our data provide a rational explanation for resistance variants local to the central drug binding site, and also highlight a potential alternative route to resistance operating within the periplasmic domain.

PubMed: 34242558
DOI: 10.1016/j.str.2021.06.013

Experimental method

ELECTRON MICROSCOPY (3 Å)