Structures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport
Abstract
The mycobacterial membrane protein large 3 (MmpL3) transporter is essential and required for shuttling the lipid trehalose monomycolate (TMM), a precursor of mycolic acid (MA)-containing trehalose dimycolate (TDM) and mycolyl arabinogalactan peptidoglycan (mAGP), in Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium smegmatis. However, the mechanism that MmpL3 uses to facilitate the transport of fatty acids and lipidic elements to the mycobacterial cell wall remains elusive. Here, we report 7 structures of the M. smegmatis MmpL3 transporter in its unbound state and in complex with trehalose 6-decanoate (T6D) or TMM using single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography. Combined with calculated results from molecular dynamics (MD) and target MD simulations, we reveal a lipid transport mechanism that involves a coupled movement of the periplasmic domain and transmembrane helices of the MmpL3 transporter that facilitates the shuttling of lipids to the mycobacterial cell wall.
- Authors:
-
[1];
[1];
[2];
[1]
- Case Western Reserve University, Cleveland, OH (United States)
- Northeastern University, Boston, MA (United States)
- Publication Date:
- Research Org.:
- Case Western Reserve Univ., Cleveland, OH (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Cancer Institute (NCI)
- OSTI Identifier:
- 1903928
- Grant/Contract Number:
- AC05-76RL01830; R01AI145069; HSSN261200800001E; U24GM129547
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS Biology (Online)
- Additional Journal Information:
- Journal Name: PLoS Biology (Online); Journal Volume: 19; Journal Issue: 8; Journal ID: ISSN 1545-7885
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; electron cryo-microscopy; lipids; membrane proteins; mycobacterium tuberculosis; fungal structure; molecular dynamics; trehalose; crystal structure
Citation Formats
Su, Chih-Chia, Klenotic, Philip A., Cui, Meng, Lyu, Meinan, Morgan, Christopher E., and Yu, Edward W. Structures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport. United States: N. p., 2021.
Web. doi:10.1371/journal.pbio.3001370.
Su, Chih-Chia, Klenotic, Philip A., Cui, Meng, Lyu, Meinan, Morgan, Christopher E., & Yu, Edward W. Structures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport. United States. https://doi.org/10.1371/journal.pbio.3001370
Su, Chih-Chia, Klenotic, Philip A., Cui, Meng, Lyu, Meinan, Morgan, Christopher E., and Yu, Edward W. Thu .
"Structures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport". United States. https://doi.org/10.1371/journal.pbio.3001370. https://www.osti.gov/servlets/purl/1903928.
@article{osti_1903928,
title = {Structures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport},
author = {Su, Chih-Chia and Klenotic, Philip A. and Cui, Meng and Lyu, Meinan and Morgan, Christopher E. and Yu, Edward W.},
abstractNote = {The mycobacterial membrane protein large 3 (MmpL3) transporter is essential and required for shuttling the lipid trehalose monomycolate (TMM), a precursor of mycolic acid (MA)-containing trehalose dimycolate (TDM) and mycolyl arabinogalactan peptidoglycan (mAGP), in Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium smegmatis. However, the mechanism that MmpL3 uses to facilitate the transport of fatty acids and lipidic elements to the mycobacterial cell wall remains elusive. Here, we report 7 structures of the M. smegmatis MmpL3 transporter in its unbound state and in complex with trehalose 6-decanoate (T6D) or TMM using single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography. Combined with calculated results from molecular dynamics (MD) and target MD simulations, we reveal a lipid transport mechanism that involves a coupled movement of the periplasmic domain and transmembrane helices of the MmpL3 transporter that facilitates the shuttling of lipids to the mycobacterial cell wall.},
doi = {10.1371/journal.pbio.3001370},
journal = {PLoS Biology (Online)},
number = 8,
volume = 19,
place = {United States},
year = {Thu Aug 12 00:00:00 EDT 2021},
month = {Thu Aug 12 00:00:00 EDT 2021}
}
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Works referenced in this record:
Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target
journal, January 2019
- Zhang, Bing; Li, Jun; Yang, Xiaolin
- Cell, Vol. 176, Issue 3
MMPBSA.py : An Efficient Program for End-State Free Energy Calculations
journal, August 2012
- Miller, Bill R.; McGee, T. Dwight; Swails, Jason M.
- Journal of Chemical Theory and Computation, Vol. 8, Issue 9
CASTp 3.0: computed atlas of surface topography of proteins
journal, June 2018
- Tian, Wei; Chen, Chang; Lei, Xue
- Nucleic Acids Research, Vol. 46, Issue W1
GROMACS: A message-passing parallel molecular dynamics implementation
journal, September 1995
- Berendsen, H. J. C.; van der Spoel, D.; van Drunen, R.
- Computer Physics Communications, Vol. 91, Issue 1-3
Tuberculosis—advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers
journal, April 2016
- Wallis, Robert S.; Maeurer, Markus; Mwaba, Peter
- The Lancet Infectious Diseases, Vol. 16, Issue 4
Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action
journal, July 2012
- Sacksteder, Katherine A.; Protopopova, Marina; Barry, Clifton E.
- Future Microbiology, Vol. 7, Issue 7
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems
journal, June 1993
- Darden, Tom; York, Darrin; Pedersen, Lee
- The Journal of Chemical Physics, Vol. 98, Issue 12
Identification of New MmpL3 Inhibitors by Untargeted and Targeted Mutant Screens Defines MmpL3 Domains with Differential Resistance
journal, August 2019
- Williams, John T.; Haiderer, Elizabeth R.; Coulson, Garry B.
- Antimicrobial Agents and Chemotherapy, Vol. 63, Issue 10
Scalable molecular dynamics with NAMD
journal, January 2005
- Phillips, James C.; Braun, Rosemary; Wang, Wei
- Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations
journal, November 2012
- Vargiu, A. V.; Nikaido, H.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 50
Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport
journal, September 2010
- Long, Feng; Su, Chih-Chia; Zimmermann, Michael T.
- Nature, Vol. 467, Issue 7314
On the convergence of the conformational coordinates basis set obtained by the essential dynamics analysis of proteins' molecular dynamics simulations
journal, September 1999
- Amadei, Andrea; Ceruso, Marc A.; Di Nola, Alfredo
- Proteins: Structure, Function, and Genetics, Vol. 36, Issue 4
Automatic atom type and bond type perception in molecular mechanical calculations
journal, October 2006
- Wang, Junmei; Wang, Wei; Kollman, Peter A.
- Journal of Molecular Graphics and Modelling, Vol. 25, Issue 2
Improvement of cryo-EM maps by density modification
journal, August 2020
- Terwilliger, Thomas C.; Ludtke, Steven J.; Read, Randy J.
- Nature Methods, Vol. 17, Issue 9
Essential dynamics of proteins
journal, December 1993
- Amadei, Andrea; Linssen, Antonius B. M.; Berendsen, Herman J. C.
- Proteins: Structure, Function, and Genetics, Vol. 17, Issue 4
MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine
journal, May 2019
- Su, Chih-Chia; Klenotic, Philip A.; Bolla, Jani Reddy
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 23
PHENIX : building new software for automated crystallographic structure determination
journal, October 2002
- Adams, Paul D.; Grosse-Kunstleve, Ralf W.; Hung, Li-Wei
- Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 11
Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane
journal, February 2012
- Grzegorzewicz, Anna E.; Pham, Ha; Gundi, Vijay A. K. B.
- Nature Chemical Biology, Vol. 8, Issue 4
MmpL Genes Are Associated with Mycolic Acid Metabolism in Mycobacteria and Corynebacteria
journal, April 2012
- Varela, Cristian; Rittmann, Doris; Singh, Albel
- Chemistry & Biology, Vol. 19, Issue 4
Improved BM212 MmpL3 Inhibitor Analogue Shows Efficacy in Acute Murine Model of Tuberculosis Infection
journal, February 2013
- Poce, Giovanna; Bates, Robert H.; Alfonso, Salvatore
- PLoS ONE, Vol. 8, Issue 2
Direct observation of the influence of cardiolipin and antibiotics on lipid II binding to MurJ
journal, January 2018
- Bolla, Jani Reddy; Sauer, Joshua B.; Wu, Di
- Nature Chemistry, Vol. 10, Issue 3
Development and testing of a general amber force field
journal, January 2004
- Wang, Junmei; Wolf, Romain M.; Caldwell, James W.
- Journal of Computational Chemistry, Vol. 25, Issue 9
Cryoelectron Microscopy Structures of AdeB Illuminate Mechanisms of Simultaneous Binding and Exporting of Substrates
journal, February 2021
- Morgan, Christopher E.; Glaza, Przemyslaw; Leus, Inga V.
- mBio, Vol. 12, Issue 1
Real-space refinement in PHENIX for cryo-EM and crystallography
journal, May 2018
- Afonine, Pavel V.; Poon, Billy K.; Read, Randy J.
- Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 6
Automated electron microscope tomography using robust prediction of specimen movements
journal, October 2005
- Mastronarde, David N.
- Journal of Structural Biology, Vol. 152, Issue 1
UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004
- Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
- Journal of Computational Chemistry, Vol. 25, Issue 13
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination
journal, February 2017
- Punjani, Ali; Rubinstein, John L.; Fleet, David J.
- Nature Methods, Vol. 14, Issue 3
[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997
- Otwinowski, Zbyszek; Minor, Wladek
- Macromolecular Crystallography Part A, 307-326
MmpL3 is the flippase for mycolic acids in mycobacteria
journal, July 2017
- Xu, Zhujun; Meshcheryakov, Vladimir A.; Poce, Giovanna
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 30
In vivo potent BM635 analogue with improved drug-like properties
journal, February 2018
- Poce, Giovanna; Cocozza, Martina; Alfonso, Salvatore
- European Journal of Medicinal Chemistry, Vol. 145
Determining atom-centered monopoles from molecular electrostatic potentials. The need for high sampling density in formamide conformational analysis
journal, April 1990
- Breneman, Curt M.; Wiberg, Kenneth B.
- Journal of Computational Chemistry, Vol. 11, Issue 3
Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection
journal, June 2016
- Stec, Jozef; Onajole, Oluseye K.; Lun, Shichun
- Journal of Medicinal Chemistry, Vol. 59, Issue 13
Gctf: Real-time CTF determination and correction
journal, January 2016
- Zhang, Kai
- Journal of Structural Biology, Vol. 193, Issue 1