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- PDB-7nvh: Cryo-EM structure of the mycolic acid transporter MmpL3 from M. t... -

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Entry
Database: PDB / ID: 7nvh
TitleCryo-EM structure of the mycolic acid transporter MmpL3 from M. tuberculosis
ComponentsTrehalose monomycolate exporter MmpL3
KeywordsMEMBRANE PROTEIN / TRANSPORTER
Function / homology
Function and homology information


phosphatidylglycerol binding / Actinobacterium-type cell wall biogenesis / diacylglycerol binding / cell tip / mycolic acid biosynthetic process / cell septum / lipopolysaccharide transport / cardiolipin binding / phosphatidylethanolamine binding / membrane => GO:0016020 ...phosphatidylglycerol binding / Actinobacterium-type cell wall biogenesis / diacylglycerol binding / cell tip / mycolic acid biosynthetic process / cell septum / lipopolysaccharide transport / cardiolipin binding / phosphatidylethanolamine binding / membrane => GO:0016020 / phosphatidylinositol binding / peptidoglycan-based cell wall / regulation of membrane potential / cell wall organization / 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
Lauryl Maltose Neopentyl Glycol / Trehalose monomycolate RND transporter MmpL3 / Trehalose monomycolate exporter MmpL3
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsAdams, O. / Deme, J.C. / Parker, J.L. / Lea, S.M. / Newstead, S.
Funding support United Kingdom, 6items
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, 2021Deposition site: PDBE / Processing site: PDBE
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Assembly

Deposited unit
A: Trehalose monomycolate exporter MmpL3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,5312
Polymers82,5261
Non-polymers1,0051
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area29260 Å2

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Components

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


Mass: 82525.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: mmpL3, Rv0206c, MTCY08D5.01c, MTV033.14c / Production host: Escherichia coli (E. coli) / References: UniProt: P9WJV5, UniProt: A0A658HT16*PLUS
#2: Chemical ChemComp-AV0 / Lauryl Maltose Neopentyl Glycol / 2,2-didecylpropane-1,3-bis-b-D-maltopyranoside / 2-decyl-2-{[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy]methyl}dodecyl4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside


Mass: 1005.188 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C47H88O22
Has ligand of interestN
Has protein modificationN

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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: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 58.2 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 414082 / Symmetry type: POINT
RefinementHighest resolution: 3 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045650
ELECTRON MICROSCOPYf_angle_d0.617693
ELECTRON MICROSCOPYf_dihedral_angle_d12.726801
ELECTRON MICROSCOPYf_chiral_restr0.044930
ELECTRON MICROSCOPYf_plane_restr0.005950

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