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- EMDB-32634: Cryo-EM structure of Mycobacterium smegmatis MmpL3 complexed with... -

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Basic information

Entry
Database: EMDB / ID: EMD-32634
TitleCryo-EM structure of Mycobacterium smegmatis MmpL3 complexed with ST004 in lipid nanodiscs
Map data
Sample
  • Complex: Mycolic acid transporter MmpL3
    • Protein or peptide: Trehalose monomycolate exporter MmpL3
  • Ligand: N-[2-(2-adamantylamino)ethyl]-1-[2,4-bis(fluoranyl)phenyl]-5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxamide
Keywordsdrug target / novel compound / Mycobacterium tuberculosis / MEMBRANE PROTEIN
Function / homology
Function and homology information


phosphatidylethanolamine transfer activity / phosphatidylglycerol binding / trehalose transmembrane transporter activity / trehalose transport / mycolate cell wall layer assembly / diacylglycerol binding / cell wall biogenesis / cell pole / cell tip / mycolic acid biosynthetic process ...phosphatidylethanolamine transfer activity / phosphatidylglycerol binding / trehalose transmembrane transporter activity / trehalose transport / mycolate cell wall layer assembly / diacylglycerol binding / cell wall biogenesis / cell pole / cell tip / mycolic acid biosynthetic process / cardiolipin binding / cell septum / phospholipid transport / phosphatidylethanolamine binding / phosphatidylinositol binding / regulation of membrane potential / 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
Trehalose monomycolate exporter MmpL3
Similarity search - Component
Biological speciesMycolicibacterium smegmatis MC2 155 (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsZhang B / Hu T
Funding support China, 4 items
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, 2022-
Header (metadata) releaseAug 3, 2022-
Map releaseAug 3, 2022-
UpdateApr 10, 2024-
Current statusApr 10, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32634.png

Downloads & links

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Map

FileDownload / File: emd_32634.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.82 Å
Density
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.3123534 - 2.1235495
Average (Standard dev.)0.00195914 (±0.082918465)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 209.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Mycolic acid transporter MmpL3

EntireName: Mycolic acid transporter MmpL3
Components
  • Complex: Mycolic acid transporter MmpL3
    • Protein or peptide: Trehalose monomycolate exporter MmpL3
  • Ligand: N-[2-(2-adamantylamino)ethyl]-1-[2,4-bis(fluoranyl)phenyl]-5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxamide

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Supramolecule #1: Mycolic acid transporter MmpL3

SupramoleculeName: Mycolic acid transporter MmpL3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria)

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Macromolecule #1: Trehalose monomycolate exporter MmpL3

MacromoleculeName: Trehalose monomycolate exporter MmpL3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria) / Strain: MC2 155
Molecular weightTheoretical: 110.056781 KDa
Recombinant expressionOrganism: Mycolicibacterium smegmatis MC2 155 (bacteria)
SequenceString: FQSNAMFAWW GRTVYQFRYI VIGVMVALCL GGGVYGISLG NHVTQSGFYD EGSQSVAASL IGDEVYGRDR TSHVVAILTP PDDKKVTDK AWQKKVTEEL DQVVKDHEDQ IVGWVGWLKA PDTTDPTVSA MKTQDLRHTF ISIPLQGDDD DEILKNYQVV E PELQQVNG ...String:
FQSNAMFAWW GRTVYQFRYI VIGVMVALCL GGGVYGISLG NHVTQSGFYD EGSQSVAASL IGDEVYGRDR TSHVVAILTP PDDKKVTDK AWQKKVTEEL DQVVKDHEDQ IVGWVGWLKA PDTTDPTVSA MKTQDLRHTF ISIPLQGDDD DEILKNYQVV E PELQQVNG GDIRLAGLNP LASELTGTIG EDQKRAEVAA IPLVAVVLFF VFGTVIAAAL PAIIGGLAIA GALGIMRLVA EF TPVHFFA QPVVTLIGLG IAIDYGLFIV SRFREEIAEG YDTEAAVRRT VMTSGRTVVF SAVIIVASSV PLLLFPQGFL KSI TYAIIA SVMLAAILSI TVLAAALAIL GPRVDALGVT TLLKIPFLAN WQFSRRIIDW FAEKTQKTKT REEVERGFWG RLVN VVMKR PIAFAAPILV VMVLLIIPLG QLSLGGISEK YLPPDNAVRQ SQEQFDKLFP GFRTEPLTLV MKREDGEPIT DAQIA DMRA KALTVSGFTD PDNDPEKMWK ERPANDSGSK DPSVRVIQNG LENRNDAAKK IDELRALQPP HGIEVFVGGT PALEQD SIH SLFDKLPLMA LILIVTTTVL MFLAFGSVVL PIKAALMSAL TLGSTMGILT WMFVDGHGSG LMNYTPQPLM APMIGLI IA VIWGLSTDYE VFLVSRMVEA RERGMSTAEA IRIGTATTGR LITGAALILA VVAGAFVFSD LVMMKYLAFG LLIALLLD A TIIRMFLVPA VMKLLGDDCW WAPRWMKRVQ EKLGLGETEL PDERKRPTVR ESETDQRALV GVGAPPPPPR PHDPTHPAP EPVRPMPPMR SNAPSAAGTA RISTPPQPPQ PPQAPAQQAG DEPATTRFAM ARNAVRNAVN SAVHGGAGSA AAPTERAPRP GGPAQPPAP PQREEREIES WLGALRGPAP AKNVPQPPAQ PQRPSTDTTR AMPPQGRPPA GPADRGNENA PTTAFSAQRP P NGGAPADA TTAIPTPPQR EQEPSTEKLN TREDAPEDPE TKRRGGGMSA QDLLRREGRL

UniProtKB: Trehalose monomycolate exporter MmpL3

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Macromolecule #2: N-[2-(2-adamantylamino)ethyl]-1-[2,4-bis(fluoranyl)phenyl]-5-(4-c...

MacromoleculeName: N-[2-(2-adamantylamino)ethyl]-1-[2,4-bis(fluoranyl)phenyl]-5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxamide
type: ligand / ID: 2 / Number of copies: 1 / Formula: 1I2
Molecular weightTheoretical: 525.032 Da
Chemical component information

ChemComp-1I2:
N-[2-(2-adamantylamino)ethyl]-1-[2,4-bis(fluoranyl)phenyl]-5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxamide

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6ajf

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 352885

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