EMD-36797
mycobacterial efflux pump, AMPPNP bound state
EMD-36797
Single-particle2.9 Å
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Map released: 17/07/2024
Last modified: 29/01/2025
Sample Organism:
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Sample: ternary complex of an ABC transporter Rv1217c-1218c
Fitted models: 8k1o (Avg. Q-score: 0.597)
Deposition Authors: Wang Y
,
Wu F
,
Zhang L
,
Rao Z
Sample: ternary complex of an ABC transporter Rv1217c-1218c
Fitted models: 8k1o (Avg. Q-score: 0.597)
Deposition Authors: Wang Y
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Cryo-EM structures of a mycobacterial ABC transporter that mediates rifampicin resistance.
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 SM,
Shui G,
Li S
,
Da L,
Guddat LW
,
Rao Z
,
Zhang L
(2024) PNAS , 121 , e2403421121 - e2403421121
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(2024) PNAS , 121 , e2403421121 - e2403421121
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, Mycobacterium tuberculosis (Mtb), has a cluster of ATP-binding cassette (ABC) transporters which are responsible for drug resistance through active export. Here, we describe studies characterizing Mtb 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.
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, Mycobacterium tuberculosis (Mtb), has a cluster of ATP-binding cassette (ABC) transporters which are responsible for drug resistance through active export. Here, we describe studies characterizing Mtb 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.