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- EMDB-12604: Cryo-EM structure of the mycolic acid transporter MmpL3 from M. t... -

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Basic information

Entry
Database: EMDB / ID: EMD-12604
TitleCryo-EM structure of the mycolic acid transporter MmpL3 from M. tuberculosis
Map datasharpened map
Sample
  • Organelle or cellular component: Mycolic acid transporter MmpL3
    • Protein or peptide: Trehalose monomycolate exporter MmpL3
  • Ligand: 2-decyl-2-{[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy]methyl}dodecyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside
Function / homology
Function and homology information


phosphatidylglycerol binding / Actinobacterium-type cell wall biogenesis / diacylglycerol binding / lipopolysaccharide transport / cell tip / mycolic acid biosynthetic process / cardiolipin binding / cell septum / phosphatidylethanolamine binding / regulation of membrane potential ...phosphatidylglycerol binding / Actinobacterium-type cell wall biogenesis / diacylglycerol binding / lipopolysaccharide transport / cell tip / mycolic acid biosynthetic process / cardiolipin binding / cell septum / phosphatidylethanolamine binding / regulation of membrane potential / phosphatidylinositol binding / peptidoglycan-based cell wall / cell wall organization / membrane => GO:0016020 / response to antibiotic / plasma membrane
Similarity search - Function
Membrane transport protein MMPL domain / MMPL family / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain
Similarity search - Domain/homology
Trehalose monomycolate RND transporter MmpL3 / Trehalose monomycolate exporter MmpL3
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsAdams O / Deme JC / Parker JL / Lea SM / Newstead S
Funding support United Kingdom, 6 items
OrganizationGrant numberCountry
Wellcome Trust201536 United Kingdom
Wellcome Trust215519 United Kingdom
Wellcome Trust219531 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/S021043/1 United Kingdom
Medical Research Council (MRC, United Kingdom)S021264 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/M011224/1 United Kingdom
CitationJournal: Structure / Year: 2021
Title: Cryo-EM structure and resistance landscape of M. tuberculosis MmpL3: An emergent therapeutic target.
Authors: Oliver Adams / Justin C Deme / Joanne L Parker / / Philip W Fowler / Susan M Lea / Simon Newstead /
Abstract: Tuberculosis (TB) is the leading cause of death from a single infectious agent and in 2019 an estimated 10 million people worldwide contracted the disease. Although treatments for TB exist, continual ...Tuberculosis (TB) is the leading cause of death from a single infectious agent and in 2019 an estimated 10 million people worldwide contracted the disease. Although treatments for TB exist, continual emergence of drug-resistant variants necessitates urgent development of novel antituberculars. An important new target is the lipid transporter MmpL3, which is required for construction of the unique cell envelope that shields Mycobacterium tuberculosis (Mtb) from the immune system. However, a structural understanding of the mutations in Mtb MmpL3 that confer resistance to the many preclinical leads is lacking, hampering efforts to circumvent resistance mechanisms. Here, we present the cryoelectron microscopy structure of Mtb MmpL3 and use it to comprehensively analyze the mutational landscape of drug resistance. Our data provide a rational explanation for resistance variants local to the central drug binding site, and also highlight a potential alternative route to resistance operating within the periplasmic domain.
History
DepositionMar 15, 2021-
Header (metadata) releaseJun 16, 2021-
Map releaseJun 16, 2021-
UpdateDec 21, 2022-
Current statusDec 21, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.5
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  • Surface view colored by height
  • Surface level: 0.5
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  • Surface view with fitted model
  • Atomic models: PDB-7nvh
  • Surface level: 0.5
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7nvh
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12604.png

Downloads & links

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Map

FileDownload / File: emd_12604.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 0.832 Å
Density
Contour LevelBy AUTHOR: 0.4 / Movie #1: 0.5
Minimum - Maximum-1.8948402 - 3.5054762
Average (Standard dev.)0.0004909449 (±0.06703866)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8320.8320.832
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z266.240266.240266.240
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-1.8953.5050.000

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Supplemental data

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Mask #1

Fileemd_12604_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: unsharpened map

Fileemd_12604_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_12604_half_map_1.map
Annotationhalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_12604_half_map_2.map
Annotationhalf map A
Projections & Slices
AxesZYX

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Sample components

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Entire : Mycolic acid transporter MmpL3

EntireName: Mycolic acid transporter MmpL3
Components
  • Organelle or cellular component: Mycolic acid transporter MmpL3
    • Protein or peptide: Trehalose monomycolate exporter MmpL3
  • Ligand: 2-decyl-2-{[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy]methyl}dodecyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside

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Supramolecule #1: Mycolic acid transporter MmpL3

SupramoleculeName: Mycolic acid transporter MmpL3 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycobacterium tuberculosis (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: Mycobacterium tuberculosis (bacteria)
Molecular weightTheoretical: 82.525609 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MFAWWGRTVY RYRFIVIGVM VALCLGGGVF GLSLGKHVTQ SGFYDDGSQS VQASVLGDQV YGRDRSGHIV AIFQAPAGKT VDDPAWSKK VVDELNRFQQ DHPDQVLGWA GYLRASQATG MATADKKYTF VSIPLKGDDD DTILNNYKAI APDLQRLDGG T VKLAGLQP ...String:
MFAWWGRTVY RYRFIVIGVM VALCLGGGVF GLSLGKHVTQ SGFYDDGSQS VQASVLGDQV YGRDRSGHIV AIFQAPAGKT VDDPAWSKK VVDELNRFQQ DHPDQVLGWA GYLRASQATG MATADKKYTF VSIPLKGDDD DTILNNYKAI APDLQRLDGG T VKLAGLQP VAEALTGTIA TDQRRMEVLA LPLVAVVLFF VFGGVIAAGL PVMVGGLCIA GALGIMRFLA IFGPVHYFAQ PV VSLIGLG IAIDYGLFIV SRFREEIAEG YDTETAVRRT VITAGRTVTF SAVLIVASAI GLLLFPQGFL KSLTYATIAS VML SAILSI TVLPACLGIL GKHVDALGVR TLFRVPFLAN WKISAAYLNW LADRLQRTKT REEVEAGFWG KLVNRVMKRP VLFA APIVI IMILLIIPVG KLSLGGISEK YLPPTNSVRQ AQEEFDKLFP GYRTNPLTLV IQTSNHQPVT DAQIADIRSK AMAIG GFIE PDNDPANMWQ ERAYAVGASK DPSVRVLQNG LINPADASKK LTELRAITPP KGITVLVGGT PALELDSIHG LFAKMP LMV VILLTTTIVL MFLAFGSVVL PIKATLMSAL TLGSTMGILT WIFVDGHFSK WLNFTPTPLT APVIGLIIAL VFGLSTD YE VFLVSRMVEA RERGMSTQEA IRIGTAATGR IITAAALIVA VVAGAFVFSD LVMMKYLAFG LMAALLLDAT VVRMFLVP S VMKLLGDDCW WAPRWARRLQ TRIGLGEIHL PDGSENLYFQ

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Macromolecule #2: 2-decyl-2-{[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy...

MacromoleculeName: 2-decyl-2-{[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy]methyl}dodecyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside
type: ligand / ID: 2 / Number of copies: 1 / Formula: AV0
Molecular weightTheoretical: 1.005188 KDa

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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

Concentration2 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 58.2 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 414082
FSC plot (resolution estimation)

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