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- PDB-6lyy: Cryo-EM structure of the human MCT1/Basigin-2 complex in the pres... -
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Basic information
Entry | Database: PDB / ID: 6lyy | ||||||
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Title | Cryo-EM structure of the human MCT1/Basigin-2 complex in the presence of anti-cancer drug candidate AZD3965 in the outward-open conformation. | ||||||
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![]() | TRANSPORT PROTEIN / Proton-coupled monocarboxylate transporter / MCT1 / Basigin / anti-cancer / AZD3965 / BAY-8002 / 7ACC2 / single particle cryo-EM / latate transporter | ||||||
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 | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | ||||||
![]() | Wang, N. / Jiang, X. / Zhang, S. / Zhu, A. / Yuan, Y. / Lei, J. / Yan, C. | ||||||
![]() | ![]() 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. | ||||||
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 114.6 KB | Display | ![]() |
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PDB format | ![]() | 81.1 KB | Display | ![]() |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 30019MC ![]() 6lz0C ![]() 7ckoC ![]() 7ckrC ![]() 7da5C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 53992.852 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Protein | Mass: 29254.938 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#3: Chemical | ChemComp-EY0 / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: MCT1/Basigin-2 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 8 Details: 25 mM Tris pH 8.0, 150 mM NaCl, and 0.02% (w/v) GDN |
Specimen | Conc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Cs: 0.01 mm |
Image recording | Electron dose: 37.6 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
Software | Name: PHENIX / Version: dev_3707: / Classification: refinement | ||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1326285 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||
Refinement | Highest resolution: 3.2 Å | ||||||||||||||||||||||||||||||||
Refine LS restraints |
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