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- EMDB-30020: Cryo-EM structure of human MCT1 in complex with Basigin-2 in the ... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-30020 | |||||||||
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Title | Cryo-EM structure of human MCT1 in complex with Basigin-2 in the presence of lactate | |||||||||
![]() | Cryo-EM structures of human MCT1 in complex with Basigin-2 in the presence of lactate. | |||||||||
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![]() | lactate transporter / MCT1 / Basigin-2 / Proton-coupled monocarboxylate transporter / TRANSPORT PROTEIN | |||||||||
Function / homology | ![]() mevalonate transmembrane transporter activity / mevalonate transport / plasma membrane lactate transport / behavioral response to nutrient / pyruvate transmembrane transport / monocarboxylic acid transmembrane transporter activity / lactate transmembrane transporter activity / monocarboxylic acid transport / lactate:proton symporter activity / Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) ...mevalonate transmembrane transporter activity / mevalonate transport / plasma membrane lactate transport / behavioral response to nutrient / pyruvate transmembrane transport / monocarboxylic acid transmembrane transporter activity / lactate transmembrane transporter activity / monocarboxylic acid transport / lactate:proton symporter activity / Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) / succinate transmembrane transport / Proton-coupled monocarboxylate transport / pyruvate catabolic process / succinate transmembrane transporter activity / positive regulation of matrix metallopeptidase secretion / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / acrosomal membrane / response to mercury ion / organic cyclic compound binding / endothelial tube morphogenesis / neural retina development / photoreceptor cell maintenance / centrosome cycle / Basigin interactions / response to food / Aspirin ADME / odontogenesis of dentin-containing tooth / D-mannose binding / regulation of insulin secretion / decidualization / cellular response to organic cyclic compound / transport across blood-brain barrier / lateral plasma membrane / photoreceptor outer segment / positive regulation of vascular endothelial growth factor production / Integrin cell surface interactions / response to cAMP / embryo implantation / neutrophil chemotaxis / Degradation of the extracellular matrix / photoreceptor inner segment / positive regulation of endothelial cell migration / basal plasma membrane / protein localization to plasma membrane / lipid metabolic process / sarcolemma / response to peptide hormone / positive regulation of interleukin-6 production / melanosome / cell junction / glucose homeostasis / virus receptor activity / signaling receptor activity / basolateral plasma membrane / angiogenesis / positive regulation of viral entry into host cell / cell surface receptor signaling pathway / endosome / cadherin binding / apical plasma membrane / Golgi membrane / intracellular membrane-bounded organelle / focal adhesion / centrosome / synapse / endoplasmic reticulum membrane / mitochondrion / extracellular exosome / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
![]() | Wang N / Jiang X | |||||||||
![]() | ![]() Title: Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Authors: Nan Wang / Xin Jiang / Shuo Zhang / Angqi Zhu / Yafei Yuan / Hanwen Xu / Jianlin Lei / Chuangye Yan / ![]() ![]() Abstract: Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their ...Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their enhanced expression in various tumors. Here, we report five cryo-EM structures, at resolutions of 3.0-3.3 Å, of human MCT1 bound to lactate or inhibitors in the presence of Basigin-2, a single transmembrane segment (TM)-containing chaperon. MCT1 exhibits similar outward-open conformations when complexed with lactate or the inhibitors BAY-8002 and AZD3965. In the presence of the inhibitor 7ACC2 or with the neutralization of the proton-coupling residue Asp309 by Asn, similar inward-open structures were captured. Complemented by structural-guided biochemical analyses, our studies reveal the substrate binding and transport mechanism of MCTs, elucidate the mode of action of three anti-cancer drug candidates, and identify the determinants for subtype-specific sensitivities to AZD3965 by MCT1 and MCT4. These findings lay out an important framework for structure-guided drug discovery targeting MCTs. | |||||||||
History |
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Structure visualization
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 28.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15 KB 15 KB | Display Display | ![]() |
Images | ![]() | 145.1 KB | ||
Filedesc metadata | ![]() | 5.6 KB | ||
Others | ![]() | 28.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6lz0MC ![]() 6lyyC ![]() 7ckoC ![]() 7ckrC ![]() 7da5C C: citing same article ( M: atomic model generated by this map |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Cryo-EM structures of human MCT1 in complex with Basigin-2 in the presence of lactate. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.087 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: Cryo-EM structures of human MCT1 in complex with...
File | emd_30020_additional_1.map | ||||||||||||
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Annotation | Cryo-EM structures of human MCT1 in complex with Basigin-2 in the presence of lactate. | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : MCT1/Basigin-2 complex in the present of lactate
Entire | Name: MCT1/Basigin-2 complex in the present of lactate |
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Components |
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-Supramolecule #1: MCT1/Basigin-2 complex in the present of lactate
Supramolecule | Name: MCT1/Basigin-2 complex in the present of lactate / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Monocarboxylate transporter 1
Macromolecule | Name: Monocarboxylate transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 53.992852 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MPPAVGGPVG YTPPDGGWGW AVVIGAFISI GFSYAFPKSI TVFFKEIEGI FHATTSEVSW ISSIMLAVMY GGGPISSILV NKYGSRIVM IVGGCLSGCG LIAASFCNTV QQLYVCIGVI GGLGLAFNLN PALTMIGKYF YKRRPLANGL AMAGSPVFLC T LAPLNQVF ...String: MPPAVGGPVG YTPPDGGWGW AVVIGAFISI GFSYAFPKSI TVFFKEIEGI FHATTSEVSW ISSIMLAVMY GGGPISSILV NKYGSRIVM IVGGCLSGCG LIAASFCNTV QQLYVCIGVI GGLGLAFNLN PALTMIGKYF YKRRPLANGL AMAGSPVFLC T LAPLNQVF FGIFGWRGSF LILGGLLLNC CVAGALMRPI GPKPTKAGKD KSKASLEKAG KSGVKKDLHD ANTDLIGRHP KQ EKRSVFQ TINQFLDLTL FTHRGFLLYL SGNVIMFFGL FAPLVFLSSY GKSQHYSSEK SAFLLSILAF VDMVARPSMG LVA NTKPIR PRIQYFFAAS VVANGVCHML APLSTTYVGF CVYAGFFGFA FGWLSSVLFE TLMDLVGPQR FSSAVGLVTI VECC PVLLG PPLLGRLNDM YGDYKYTYWA CGVVLIISGI YLFIGMGINY RLLAKEQKAN EQKKESKEEE TSIDVAGKPN EVTKA AESP DQKDTDGGPK EEESPV UniProtKB: Monocarboxylate transporter 1 |
-Macromolecule #2: Basigin
Macromolecule | Name: Basigin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 29.254938 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MAAALFVLLG FALLGTHGAS GAAGTVFTTV EDLGSKILLT CSLNDSATEV TGHRWLKGGV VLKEDALPGQ KTEFKVDSDD QWGEYSCVF LPEPMGTANI QLHGPPRVKA VKSSEHINEG ETAMLVCKSE SVPPVTDWAW YKITDSEDKA LMNGSESRFF V SSSQGRSE ...String: MAAALFVLLG FALLGTHGAS GAAGTVFTTV EDLGSKILLT CSLNDSATEV TGHRWLKGGV VLKEDALPGQ KTEFKVDSDD QWGEYSCVF LPEPMGTANI QLHGPPRVKA VKSSEHINEG ETAMLVCKSE SVPPVTDWAW YKITDSEDKA LMNGSESRFF V SSSQGRSE LHIENLNMEA DPGQYRCNGT SSKGSDQAII TLRVRSHLAA LWPFLGIVAE VLVLVTIIFI YEKRRKPEDV LD DDDAGSA PLKSSGQHQN DKGKNVRQRN SS UniProtKB: Basigin |
-Macromolecule #3: (2S)-2-HYDROXYPROPANOIC ACID
Macromolecule | Name: (2S)-2-HYDROXYPROPANOIC ACID / type: ligand / ID: 3 / Number of copies: 1 / Formula: 2OP |
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Molecular weight | Theoretical: 90.078 Da |
Chemical component information | ![]() ChemComp-2OP: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 5 mg/mL |
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Buffer | pH: 8 Details: 25 mM Tris pH 8.0, 150 mM NaCl, and 0.02% (w/v) GDN |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 37.6 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.07) / Number images used: 843599 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.07) |
Final angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.12) |