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Yorodumi- EMDB-32634: Cryo-EM structure of Mycobacterium smegmatis MmpL3 complexed with... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-32634 | |||||||||||||||
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Title | Cryo-EM structure of Mycobacterium smegmatis MmpL3 complexed with ST004 in lipid nanodiscs | |||||||||||||||
Map data | ||||||||||||||||
Sample |
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Keywords | drug 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 / cell septum / phospholipid transport / phosphatidylethanolamine binding / cardiolipin binding / phosphatidylinositol binding / regulation of membrane potential / cell wall organization / response to xenobiotic stimulus / response to antibiotic / plasma membrane Similarity search - Function | |||||||||||||||
Biological species | Mycolicibacterium smegmatis MC2 155 (bacteria) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.36 Å | |||||||||||||||
Authors | Zhang B / Hu T | |||||||||||||||
Funding support | China, 4 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_32634.map.gz | 59.2 MB | EMDB map data format | |
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Header (meta data) | emd-32634-v30.xml emd-32634.xml | 11.5 KB 11.5 KB | Display Display | EMDB header |
Images | emd_32634.png | 91.6 KB | ||
Filedesc metadata | emd-32634.cif.gz | 5.7 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-32634 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-32634 | HTTPS FTP |
-Validation report
Summary document | emd_32634_validation.pdf.gz | 592.6 KB | Display | EMDB validaton report |
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Full document | emd_32634_full_validation.pdf.gz | 592.1 KB | Display | |
Data in XML | emd_32634_validation.xml.gz | 6.2 KB | Display | |
Data in CIF | emd_32634_validation.cif.gz | 7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-32634 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-32634 | HTTPS FTP |
-Related structure data
Related structure data | 7wnxMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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-Map
File | Download / File: emd_32634.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.82 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
-Entire : Mycolic acid transporter MmpL3
Entire | Name: Mycolic acid transporter MmpL3 |
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Components |
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-Supramolecule #1: Mycolic acid transporter MmpL3
Supramolecule | Name: Mycolic acid transporter MmpL3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Mycolicibacterium smegmatis MC2 155 (bacteria) |
-Macromolecule #1: Trehalose monomycolate exporter MmpL3
Macromolecule | Name: Trehalose monomycolate exporter MmpL3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mycolicibacterium smegmatis MC2 155 (bacteria) / Strain: MC2 155 |
Molecular weight | Theoretical: 110.056781 KDa |
Recombinant expression | Organism: Mycolicibacterium smegmatis MC2 155 (bacteria) |
Sequence | String: 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 |
-Macromolecule #2: N-[2-(2-adamantylamino)ethyl]-1-[2,4-bis(fluoranyl)phenyl]-5-(4-c...
Macromolecule | Name: 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 |
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Molecular weight | Theoretical: 525.032 Da |
Chemical component information | ChemComp-1I2: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 352885 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |