Cryo-EM structure of the trehalose monomycolate transporter, MmpL3, reconstituted into peptidiscs
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Cryo-EM structure of the trehalose monomycolate transporter, MmpL3, reconstituted into peptidiscs. / Couston, Julie; Guo, Zongxin; Wang, Kaituo; Gourdon, Pontus; Blaise, Mickaël.
I: Current Research in Structural Biology, Bind 6, 100109, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Cryo-EM structure of the trehalose monomycolate transporter, MmpL3, reconstituted into peptidiscs
AU - Couston, Julie
AU - Guo, Zongxin
AU - Wang, Kaituo
AU - Gourdon, Pontus
AU - Blaise, Mickaël
N1 - Publisher Copyright: © 2023 The Authors
PY - 2023
Y1 - 2023
N2 - Mycobacteria have an atypical thick and waxy cell wall. One of the major building blocks of such mycomembrane is trehalose monomycolate (TMM). TMM is a mycolic acid ester of trehalose that possesses long acyl chains with up to 90 carbon atoms. TMM represents an essential component of mycobacteria and is synthesized in the cytoplasm, and then flipped over the plasma membrane by a specific transporter known as MmpL3. Over the last decade, MmpL3 has emerged as an attractive drug target to combat mycobacterial infections. Recent three-dimensional structures of MmpL3 determined by X-ray crystallography and cryo-EM have increased our understanding of the TMM transport, and the mode of action of inhibiting compounds. These structures were obtained in the presence of detergent and/or in a lipidic environment. In this study, we demonstrate the possibility of obtaining a high-quality cryo-EM structure of MmpL3 without any presence of detergent through the reconstitution of the protein into peptidiscs. The structure was determined at an overall resolution of 3.2 Å and demonstrates that the overall structure of MmpL3 is preserved as compared to previous structures. Further, the study identified a new structural arrangement of the linker that fuses the two subdomains of the transmembrane domain, suggesting the feature may serve a role in the transport process.
AB - Mycobacteria have an atypical thick and waxy cell wall. One of the major building blocks of such mycomembrane is trehalose monomycolate (TMM). TMM is a mycolic acid ester of trehalose that possesses long acyl chains with up to 90 carbon atoms. TMM represents an essential component of mycobacteria and is synthesized in the cytoplasm, and then flipped over the plasma membrane by a specific transporter known as MmpL3. Over the last decade, MmpL3 has emerged as an attractive drug target to combat mycobacterial infections. Recent three-dimensional structures of MmpL3 determined by X-ray crystallography and cryo-EM have increased our understanding of the TMM transport, and the mode of action of inhibiting compounds. These structures were obtained in the presence of detergent and/or in a lipidic environment. In this study, we demonstrate the possibility of obtaining a high-quality cryo-EM structure of MmpL3 without any presence of detergent through the reconstitution of the protein into peptidiscs. The structure was determined at an overall resolution of 3.2 Å and demonstrates that the overall structure of MmpL3 is preserved as compared to previous structures. Further, the study identified a new structural arrangement of the linker that fuses the two subdomains of the transmembrane domain, suggesting the feature may serve a role in the transport process.
KW - Cryo-EM
KW - MmpL3
KW - Mycobacteria
KW - Peptidiscs
KW - Trehalose monomycolate
U2 - 10.1016/j.crstbi.2023.100109
DO - 10.1016/j.crstbi.2023.100109
M3 - Journal article
C2 - 38034087
AN - SCOPUS:85178925167
VL - 6
JO - Current Research in Structural Biology
JF - Current Research in Structural Biology
SN - 2665-928X
M1 - 100109
ER -
ID: 377451285