Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 2 min ago
Peer-reviewedCC BY 4.0PLOS Computational Biology

Proton transport drives allosteric conformational changes in the MmpL3 transporter

  • Lixinhao Yang1
  • E. Jeffrey North2
  • Helen I. Zgurskaya3
  • Mary Jackson4
  • James C. Gumbart1,5
5 affiliations
  1. 1School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, United States of America
  2. 2Department of Pharmacy Sciences, Creighton University, Omaha, Nebraska, United States of America
  3. 3Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, United States of America
  4. 4Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America
  5. 5School of Physics, Georgia Institute of Technology, Atlanta, Georgia, United States of America
Read full textPDFDOICite

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis, further complicated by increasing drug resistance. The mycobacterial membrane protein MmpL3, which is essential for transporting cell wall precursors such as trehalose monomycolate (TMM), is a promising therapeutic target. However, the mechanistic link between proton-driven dynamics and substrate transport in MmpL3 is not fully understood. In this study, we use molecular dynamics simulations to investigate how protonation of conserved Asp-Tyr dyads (Asp256-Tyr646 and Asp645-Tyr257) in Mycobacterium smegmatis (Msmg) MmpL3 regulates conformational changes and TMM binding. Protonation at Asp256 induces an open dyad conformation, increases local water accessibility, and is associated with a tendency toward more open configurations of the periplasmic binding pocket. In contrast, protonation at Asp645 stabilizes a closed dyad conformation, reduces water accessibility, and narrows the transmembrane binding pocket. These findings support a proposed sequential protonation model in which protonation-dependent conformational changes are allosterically coupled to substrate translocation. Author summary: Tuberculosis remains one of the deadliest infectious diseases worldwide, in part because the bacterium builds an unusually strong cell wall that is difficult for drugs to penetrate. MmpL3 is essential for assembling this cell wall and is therefore an important target for new drugs. However, it has not been clear how this transporter uses protons to power lipid movement. In this work, we used molecular dynamics simulations to examine how protonation at two conserved sites controls the structure and behavior of MmpL3. We focused on two conserved sites inside the protein and found that protonation at each site produces different structural effects. One protonation state favors a more open and hydrated local environment, while the other favors a more closed and less hydrated configuration. These changes support a stepwise mechanism in which protonation acts as a molecular switch to coordinate transport. By clarifying how proton-driven conformational changes power MmpL3 function, our work provides insight into a critical process in mycobacterial cell wall construction and may help guide future efforts to develop new tuberculosis therapies.

Related

  1. Trans-Allosteric Activation Releases Distinct Conformational Traps in Kinase Heterodimers
    A. Imamoto, Y. Wu, A. Shinobu +1
    bioRxivPreprintCC BYFull textBiophysicsbioRxiv
  2. Structure Basis for Chloride Recognition and Transport by Human Kidney Brain Anion Transporter (KBAT)
    Yurou Wang, Tengyu Xie, Songyue Wu +5
    BiomoleculesPeer-reviewedCC BYFull textGeneral biochemistryEurope PMC
  3. Electrostatic control of conformational dynamics drives proton translocation in respiratory Complex I
    J. Liebau, P. Saura, S. Badolato +2
    bioRxivPreprintCC BY-NC-NDFull textBiophysicsbioRxiv
  4. Molecular dynamics analysis of T567 phosphorylation-induced conformational changes in ezrin.
    Sai Li, Jinmei Pan, Lirui Lin +5
    Current research in structural biologyPeer-reviewedCC BY-NC-NDFull textMolecular biology & gene regulationEurope PMC
  5. Measuring protein conformational changes with genetically encoded bipyridylalanine and transition-metal ion FRET
    C. DeFreest, E. M. Carmona, S. E. Gordon +1
    bioRxivPreprintCC BYFull textBiophysicsbioRxiv

Cite

BibTeXRIS
BibTeX
@article{yang2026proton,
  title = {{Proton transport drives allosteric conformational changes in the MmpL3 transporter}},
  author = {Lixinhao Yang and E. Jeffrey North and Helen I. Zgurskaya and Mary Jackson and James C. Gumbart},
  journal = {PLOS Computational Biology},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pcbi.1014880},
  url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014880},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Proton transport drives allosteric conformational changes in the MmpL3 transporter
AU  - Lixinhao Yang
AU  - E. Jeffrey North
AU  - Helen I. Zgurskaya
AU  - Mary Jackson
AU  - James C. Gumbart
PY  - 2026
DA  - 2026/10/21
JO  - PLOS Computational Biology
DO  - 10.1371/journal.pcbi.1014880
UR  - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014880
AB  - Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis, further complicated by increasing drug resistance. The mycobacterial membrane protein MmpL3, which is essential for transporting cell wall precursors such as trehalose monomycolate (TMM), is a promising therapeutic target. However, the mechanistic link between proton-driven dynamics and substrate transport in MmpL3 is not fully understood. In this study, we use molecular dynamics simulations to investigate how protonation of conserved Asp-Tyr dyads (Asp256-Tyr646 and Asp645-Tyr257) in Mycobacterium smegmatis (Msmg) MmpL3 regulates conformational changes and TMM binding. Protonation at Asp256 induces an open dyad conformation, increases local water accessibility, and is associated with a tendency toward more open configurations of the periplasmic binding pocket. In contrast, protonation at Asp645 stabilizes a closed dyad conformation, reduces water accessibility, and narrows the transmembrane binding pocket. These findings support a proposed sequential protonation model in which protonation-dependent conformational changes are allosterically coupled to substrate translocation. Author summary: Tuberculosis remains one of the deadliest infectious diseases worldwide, in part because the bacterium builds an unusually strong cell wall that is difficult for drugs to penetrate. MmpL3 is essential for assembling this cell wall and is therefore an important target for new drugs. However, it has not been clear how this transporter uses protons to power lipid movement. In this work, we used molecular dynamics simulations to examine how protonation at two conserved sites controls the structure and behavior of MmpL3. We focused on two conserved sites inside the protein and found that protonation at each site produces different structural effects. One protonation state favors a more open and hydrated local environment, while the other favors a more closed and less hydrated configuration. These changes support a stepwise mechanism in which protonation acts as a molecular switch to coordinate transport. By clarifying how proton-driven conformational changes power MmpL3 function, our work provides insight into a critical process in mycobacterial cell wall construction and may help guide future efforts to develop new tuberculosis therapies.
SN  - 1553-7358
SN  - 1553-734X
ER  -