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- PDB-7wnx: Cryo-EM structure of Mycobacterium smegmatis MmpL3 complexed with... -

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Entry
Database: PDB / ID: 7wnx
TitleCryo-EM structure of Mycobacterium smegmatis MmpL3 complexed with ST004 in lipid nanodiscs
ComponentsTrehalose monomycolate exporter MmpL3
KeywordsMEMBRANE PROTEIN / drug target / novel compound / Mycobacterium tuberculosis
Function / homology
Function and homology information


phosphatidylethanolamine transfer activity / phosphatidylglycerol binding / trehalose transmembrane transporter activity / trehalose transport / mycolate cell wall layer assembly / cell wall biogenesis / diacylglycerol binding / cell pole / cell tip / mycolic acid biosynthetic process ...phosphatidylethanolamine transfer activity / phosphatidylglycerol binding / trehalose transmembrane transporter activity / trehalose transport / mycolate cell wall layer assembly / cell wall biogenesis / diacylglycerol binding / cell pole / cell tip / mycolic acid biosynthetic process / cardiolipin binding / cell septum / phosphatidylethanolamine binding / phospholipid transport / regulation of membrane potential / phosphatidylinositol binding / cell wall organization / response to xenobiotic stimulus / response to antibiotic / plasma membrane
Similarity search - Function
Membrane transport protein MMPL domain / MMPL family
Similarity search - Domain/homology
Chem-1I2 / Trehalose monomycolate exporter MmpL3
Similarity search - Component
Biological speciesMycolicibacterium smegmatis MC2 155 (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsZhang, B. / Hu, T. / Yang, X. / Liu, F. / Rao, Z.
Funding support China, 4items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81520108019 China
National Natural Science Foundation of China (NSFC)81772204 China
National Natural Science Foundation of China (NSFC)32171217 China
Ministry of Science and Technology (MoST, China)2017YFC0840300 China
CitationJournal: Structure / Year: 2022
Title: Structure-based design of anti-mycobacterial drug leads that target the mycolic acid transporter MmpL3.
Authors: Tianyu Hu / Xiaolin Yang / Fengjiang Liu / Shan Sun / Zhiqi Xiong / Jingxi Liang / Xiaobao Yang / Haofeng Wang / Xiuna Yang / Luke W Guddat / Haitao Yang / Zihe Rao / Bing Zhang /
Abstract: New anti-tubercular agents are urgently needed to address the emerging threat of drug resistance to human tuberculosis. Here, we have used structure-assisted methods to develop compounds that target ...New anti-tubercular agents are urgently needed to address the emerging threat of drug resistance to human tuberculosis. Here, we have used structure-assisted methods to develop compounds that target mycobacterial membrane protein large 3 (MmpL3). MmpL3 is essential for the transport of mycolic acids, an important cell-wall component of mycobacteria. We prepared compounds that potently inhibit the growth of Mycobacterium tuberculosis (Mtb) and other mycobacteria in cell culture. The cryoelectron microscopy (cryo-EM) structure of mycobacterial MmpL3 in complex with one of these compounds (ST004) was determined using lipid nanodiscs at an overall resolution of 3.36 Å. The structure reveals the binding mode of ST004 to MmpL3, with the S4 and S5 subsites of the inhibitor-binding pocket in the proton translocation channel playing vital roles. These data are a promising starting point for the development of anti-tuberculosis drugs that target MmpL3.
History
DepositionJan 20, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Trehalose monomycolate exporter MmpL3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,5822
Polymers110,0571
Non-polymers5251
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area33010 Å2

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Components

#1: Protein Trehalose monomycolate exporter MmpL3 / TMM exporter MmpL3 / MmpL3 transporter / Mycobacterial membrane protein large 3


Mass: 110056.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycolicibacterium smegmatis MC2 155 (bacteria)
Strain: MC2 155 / Gene: mmpL3
Production host: Mycolicibacterium smegmatis MC2 155 (bacteria)
References: UniProt: A0QP27
#2: Chemical ChemComp-1I2 / N-[2-(2-adamantylamino)ethyl]-1-[2,4-bis(fluoranyl)phenyl]-5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxamide


Mass: 525.032 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31ClF2N4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Mycolic acid transporter MmpL3 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria)
Source (recombinant)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 352885 / Symmetry type: POINT

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