8K1O

mycobacterial efflux pump, AMPPNP bound state

Summary for 8K1O

• Entry DOI: 10.2210/pdb8k1o/pdb
• EMDB information: 36797
• Descriptor: Multidrug efflux system permease protein Rv1217c, Multidrug efflux system ATP-binding protein Rv1218c, CARDIOLIPIN, ... (5 entities in total)
• Functional Keywords: abc transporter, efflux pump, transport protein
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 3
• Total formula weight: 127669.29

Authors

Wang, Y.,Wu, F.,Zhang, L.,Rao, Z. (deposition date: 2023-07-11, release date: 2024-07-17, Last modification date: 2025-07-16)

Primary citation

Wang, Y.,Gao, S.,Wu, F.,Gong, Y.,Mu, N.,Wei, C.,Wu, C.,Wang, J.,Yan, N.,Yang, H.,Zhang, Y.,Liu, J.,Wang, Z.,Yang, X.,Lam, S.M.,Shui, G.,Li, S.,Da, L.,Guddat, L.W.,Rao, Z.,Zhang, L.
Cryo-EM structures of a mycobacterial ABC transporter that mediates rifampicin resistance.
Proc.Natl.Acad.Sci.USA, 121:e2403421121-e2403421121, 2024

PubMed Abstract: Drug-resistant Tuberculosis (TB) is a global public health problem. Resistance to rifampicin, the most effective drug for TB treatment, is a major growing concern. The etiological agent, (), has a cluster of ATP-binding cassette (ABC) transporters which are responsible for drug resistance through active export. Here, we describe studies characterizing Rv1217c-1218c as an ABC transporter that can mediate mycobacterial resistance to rifampicin and have determined the cryo-electron microscopy structures of Rv1217c-1218c. The structures show Rv1217c-1218c has a type V exporter fold. In the absence of ATP, Rv1217c-1218c forms a periplasmic gate by two juxtaposed-membrane helices from each transmembrane domain (TMD), while the nucleotide-binding domains (NBDs) form a partially closed dimer which is held together by four salt-bridges. Adenylyl-imidodiphosphate (AMPPNP) binding induces a structural change where the NBDs become further closed to each other, which downstream translates to a closed conformation for the TMDs. AMPPNP binding results in the collapse of the outer leaflet cavity and the opening of the periplasmic gate, which was proposed to play a role in substrate export. The rifampicin-bound structure shows a hydrophobic and periplasm-facing cavity is involved in rifampicin binding. Phospholipid molecules are observed in all determined structures and form an integral part of the Rv1217c-1218c transporter system. Our results provide a structural basis for a mycobacterial ABC exporter that mediates rifampicin resistance, which can lead to different insights into combating rifampicin resistance.

PubMed: 39226350
DOI: 10.1073/pnas.2403421121

Experimental method

ELECTRON MICROSCOPY (2.9 Å)