Structure-based design of anti-mycobacterial drug leads that target the mycolic acid transporter MmpL3

Hu, Tianyu; Yang, Xiaolin; Liu, Fengjiang; Sun, Shan; Xiong, Zhi‐Qi; Liang, Jingxi; Yang, Xiaobao; Wang, Haofeng; Yang, Xiuna; Guddat, Luke W.; Yang, Haitao; Rao, Zihe; Zhang, Bing

doi:10.1016/j.str.2022.07.009

Cited by 6 publications

(3 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structures of several key proteins of Mtb have been elucidated, e.g., membrane transporter MmpL3 [82,83], RNase J [84], fatty acyl-AMP ligase FadD32 [85], acetyltransferase Eis [86], EF-Tu/EF-Ts [49], EF-G [68], and nucleoside triphosphate pyrophosphohydrolase MazG [87]. Inhibitors of these proteins are considered promising for the treatment of tuberculosis, among which 11 potential anti-tuberculosis drugs have been obtained by Li et al, based on the rational drug of acetyltransferase Eis [86].…”

Section: Computer-aided Structure-based Anti-tuberculosis Drug Designmentioning

confidence: 99%

“…Inhibitors of these proteins are considered promising for the treatment of tuberculosis, among which 11 potential anti-tuberculosis drugs have been obtained by Li et al, based on the rational drug of acetyltransferase Eis [86]. Hu et al designed anti-mycobacterial drugs that target MmpL3 using a structure-based drug design [83]. Translation elongation factors have been considered key drug targets.…”

Section: Computer-aided Structure-based Anti-tuberculosis Drug Designmentioning

confidence: 99%

See 1 more Smart Citation

The Structural and Molecular Mechanisms of Mycobacterium tuberculosis Translational Elongation Factor Proteins

Fang,

Wu,

Duan

et al. 2024

Molecules

View full text Add to dashboard Cite

Targeting translation factor proteins holds promise for developing innovative anti-tuberculosis drugs. During protein translation, many factors cause ribosomes to stall at messenger RNA (mRNA). To maintain protein homeostasis, bacteria have evolved various ribosome rescue mechanisms, including the predominant trans-translation process, to release stalled ribosomes and remove aberrant mRNAs. The rescue systems require the participation of translation elongation factor proteins (EFs) and are essential for bacterial physiology and reproduction. However, they disappear during eukaryotic evolution, which makes the essential proteins and translation elongation factors promising antimicrobial drug targets. Here, we review the structural and molecular mechanisms of the translation elongation factors EF-Tu, EF-Ts, and EF-G, which play essential roles in the normal translation and ribosome rescue mechanisms of Mycobacterium tuberculosis (Mtb). We also briefly describe the structure-based, computer-assisted study of anti-tuberculosis drugs.

show abstract

Section: Computer-aided Structure-based Anti-tuberculosis Drug Designmentioning

confidence: 99%

Section: Computer-aided Structure-based Anti-tuberculosis Drug Designmentioning

confidence: 99%

The Structural and Molecular Mechanisms of Mycobacterium tuberculosis Translational Elongation Factor Proteins

Fang,

Wu,

Duan

et al. 2024

Molecules

View full text Add to dashboard Cite

show abstract

“…Three-dimensional structures of the apo forms of MmpL3 solved either by X-ray crystallography or cryo-EM as well as in complex with TMM or MmpL3 inhibitors shed light on the mechanism of TMM transport and its inhibition. To date sixteen three-dimensional structures of MmpL3 from Mycobacterium smegmatis (hereafter MmpL3 Msm ) were solved of which nine were determined by X-ray crystallography and seven by cryo-EM, all of the latter were reconstituted in lipid nanodiscs ( Hu et al, 2022 ; Su et al, 2019 , 2021 ; Yang et al, 2020 ; Zhang et al, 2019 ). One additional MmpL3 structure from Mtb was solved by cryo-EM ( Adams et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of the trehalose monomycolate transporter, MmpL3, reconstituted into peptidiscs

Couston,

Guo,

Wang

et al. 2023

Current Research in Structural Biology

View full text Add to dashboard Cite

Inhibitor binding and disruption of coupled motions in MmpL3 protein: Unraveling the mechanism of trehalose monomycolate transport

Zhao,

Liu,

Tong

et al. 2024

Protein Science

View full text Add to dashboard Cite

Mycobacterial membrane protein Large 3 (MmpL3) of Mycobacterium tuberculosis (Mtb) is crucial for the translocation of trehalose monomycolate (TMM) across the inner bacterial cell membrane, making it a promising target for anti‐tuberculosis (TB) drug development. While several structural, microbiological, and in vitro studies have provided significant insights, the precise mechanisms underlying TMM transport by MmpL3 and its inhibition remain incompletely understood at the atomic level. In this study, molecular dynamic (MD) simulations for the apo form and seven inhibitor‐bound forms of Mtb MmpL3 were carried out to obtain a thorough comprehension of the protein's dynamics and function. MD simulations revealed that the seven inhibitors in this work stably bind to the central channel of the transmembrane domain and primarily forming hydrogen bonds with ASP251, ASP640, or both residues. Through dynamical cross‐correlation matrix and principal component analysis analyses, several types of coupled motions between different domains were observed in the apo state, and distinct conformational states were identified using Markov state model analysis. These coupled motions and varied conformational states likely contribute to the transport of TMM. However, simulations of inhibitor‐bound MmpL3 showed an enlargement of the proton channel, potentially disrupting coupled motions. This indicates that inhibitors may impair MmpL3's transport function by directly blocking the proton channel, thereby hindering coordinated domain movements and indirectly affecting TMM translocation.

show abstract

Structure-based design of anti-mycobacterial drug leads that target the mycolic acid transporter MmpL3

Cited by 6 publications

References 46 publications

The Structural and Molecular Mechanisms of Mycobacterium tuberculosis Translational Elongation Factor Proteins

The Structural and Molecular Mechanisms of Mycobacterium tuberculosis Translational Elongation Factor Proteins

Cryo-EM structure of the trehalose monomycolate transporter, MmpL3, reconstituted into peptidiscs

Inhibitor binding and disruption of coupled motions in MmpL3 protein: Unraveling the mechanism of trehalose monomycolate transport

Contact Info

Product

Resources

About