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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-23919 | |||||||||
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Title | Cryo-EM structure of 2:2 c-MET/HGF holo-complex | |||||||||
![]() | Cryo-EM map of 2:2 c-MET/HGF holo-complex. | |||||||||
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Function / homology | ![]() regulation of p38MAPK cascade / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / skeletal muscle cell proliferation / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins ...regulation of p38MAPK cascade / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / skeletal muscle cell proliferation / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / hepatocyte growth factor receptor signaling pathway / semaphorin receptor activity / MET receptor recycling / pancreas development / MET activates PTPN11 / MET activates RAP1 and RAC1 / myoblast proliferation / Sema4D mediated inhibition of cell attachment and migration / MET activates PI3K/AKT signaling / negative regulation of stress fiber assembly / positive regulation of endothelial cell chemotaxis / negative regulation of Rho protein signal transduction / MET activates PTK2 signaling / cellular response to hepatocyte growth factor stimulus / positive regulation of DNA biosynthetic process / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of thrombin-activated receptor signaling pathway / chemoattractant activity / negative regulation of release of cytochrome c from mitochondria / negative regulation of peptidyl-serine phosphorylation / negative regulation of interleukin-6 production / positive regulation of interleukin-10 production / semaphorin-plexin signaling pathway / epithelial to mesenchymal transition / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / establishment of skin barrier / positive regulation of osteoblast differentiation / MET activates RAS signaling / phagocytosis / MECP2 regulates neuronal receptors and channels / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of microtubule polymerization / Interleukin-7 signaling / negative regulation of autophagy / cell chemotaxis / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / platelet alpha granule lumen / liver development / epithelial cell proliferation / molecular function activator activity / growth factor activity / cell morphogenesis / Negative regulation of MET activity / receptor protein-tyrosine kinase / neuron differentiation / negative regulation of inflammatory response / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / Platelet degranulation / PIP3 activates AKT signaling / mitotic cell cycle / nervous system development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / postsynapse / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / receptor complex / positive regulation of cell migration / positive regulation of protein phosphorylation / signaling receptor binding / negative regulation of apoptotic process / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / ATP binding / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.8 Å | |||||||||
![]() | Uchikawa E / Chen ZM / Xiao GY / Zhang XW / Bai XC | |||||||||
![]() | ![]() Title: Structural basis of the activation of c-MET receptor. Authors: Emiko Uchikawa / Zhiming Chen / Guan-Yu Xiao / Xuewu Zhang / Xiao-Chen Bai / ![]() ![]() Abstract: The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. Aberrant activation of c-MET can lead to both tumors growth and metastatic ...The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. Aberrant activation of c-MET can lead to both tumors growth and metastatic progression of cancer cells. C-MET can be activated by either hepatocyte growth factor (HGF), or its natural isoform NK1. Here, we report the cryo-EM structures of c-MET/HGF and c-MET/NK1 complexes in the active state. The c-MET/HGF complex structure reveals that, by utilizing two distinct interfaces, one HGF molecule is sufficient to induce a specific dimerization mode of c-MET for receptor activation. The binding of heparin as well as a second HGF to the 2:1 c-MET:HGF complex further stabilize this active conformation. Distinct to HGF, NK1 forms a stable dimer, and bridges two c-METs in a symmetrical manner for activation. Collectively, our studies provide structural insights into the activation mechanisms of c-MET, and reveal how two isoforms of the same ligand use dramatically different mechanisms to activate the receptor. | |||||||||
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 | ![]() | 70.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13.3 KB 13.3 KB | Display Display | ![]() |
Images | ![]() | 181.7 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7mo7MC ![]() 7mo8C ![]() 7mo9C ![]() 7moaC ![]() 7mobC M: atomic model generated by this map C: citing same article ( |
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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 map of 2:2 c-MET/HGF holo-complex. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : 2:2 c-MET/HGF holo-complex
Entire | Name: 2:2 c-MET/HGF holo-complex |
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Components |
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-Supramolecule #1: 2:2 c-MET/HGF holo-complex
Supramolecule | Name: 2:2 c-MET/HGF holo-complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
-Macromolecule #1: Hepatocyte growth factor
Macromolecule | Name: Hepatocyte growth factor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 83.249828 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MWVTKLLPAL LLQHVLLHLL LLPIAIPYAE GQRKRRNTIH EFKKSAKTTL IKIDPALKIK TKKVNTADQC ANRCTRNKGL PFTCKAFVF DKARKQCLWF PFNSMSSGVK KEFGHEFDLY ENKDYIRNCI IGKGRSYKGT VSITKSGIKC QPWSSMIPHE H SFLPSSYR ...String: MWVTKLLPAL LLQHVLLHLL LLPIAIPYAE GQRKRRNTIH EFKKSAKTTL IKIDPALKIK TKKVNTADQC ANRCTRNKGL PFTCKAFVF DKARKQCLWF PFNSMSSGVK KEFGHEFDLY ENKDYIRNCI IGKGRSYKGT VSITKSGIKC QPWSSMIPHE H SFLPSSYR GKDLQENYCR NPRGEEGGPW CFTSNPEVRY EVCDIPQCSE VECMTCNGES YRGLMDHTES GKICQRWDHQ TP HRHKFLP ERYPDKGFDD NYCRNPDGQP RPWCYTLDPH TRWEYCAIKT CADNTMNDTD VPLETTECIQ GQGEGYRGTV NTI WNGIPC QRWDSQYPHE HDMTPENFKC KDLRENYCRN PDGSESPWCF TTDPNIRVGY CSQIPNCDMS HGQDCYRGNG KNYM GNLSQ TRSGLTCSMW DKNMEDLHRH IFWEPDASKL NENYCRNPDD DAHGPWCYTG NPLIPWDYCP ISRCEGDTTP TIVNL DHPV ISCAKTKQLR VVNGIPTRTN IGWMVSLRYR NKHICGGSLI KESWVLTARQ CFPSRDLKDY EAWLGIHDVH GRGDEK CKQ VLNVSQLVYG PEGSDLVLMK LARPAVLDDF VSTIDLPNYG CTIPEKTSCS VYGWGYTGLI NYDGLLRVAH LYIMGNE KC SQHHRGKVTL NESEICAGAE KIGSGPCEGD YGGPLVCEQH KMRMVLGVIV PGRGCAIPNR PGIFVRVAYY AKWIHKII L TYKVPQS |
-Macromolecule #2: Hepatocyte growth factor receptor
Macromolecule | Name: Hepatocyte growth factor receptor / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 155.720625 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MKAPAVLAPG ILVLLFTLVQ RSNGECKEAL AKSEMNVNMK YQLPNFTAET PIQNVILHEH HIFLGATNYI YVLNEEDLQK VAEYKTGPV LEHPDCFPCQ DCSSKANLSG GVWKDNINMA LVVDTYYDDQ LISCGSVNRG TCQRHVFPHN HTADIQSEVH C IFSPQIEE ...String: MKAPAVLAPG ILVLLFTLVQ RSNGECKEAL AKSEMNVNMK YQLPNFTAET PIQNVILHEH HIFLGATNYI YVLNEEDLQK VAEYKTGPV LEHPDCFPCQ DCSSKANLSG GVWKDNINMA LVVDTYYDDQ LISCGSVNRG TCQRHVFPHN HTADIQSEVH C IFSPQIEE PSQCPDCVVS ALGAKVLSSV KDRFINFFVG NTINSSYFPD HPLHSISVRR LKETKDGFMF LTDQSYIDVL PE FRDSYPI KYVHAFESNN FIYFLTVQRE TLDAQTFHTR IIRFCSINSG LHSYMEMPLE CILTEKRKKR STKKEVFNIL QAA YVSKPG AQLARQIGAS LNDDILFGVF AQSKPDSAEP MDRSAMCAFP IKYVNDFFNK IVNKNNVRCL QHFYGPNHEH CFNR TLLRN SSGCEARRDE YRTEFTTALQ RVDLFMGQFS EVLLTSISTF IKGDLTIANL GTSEGRFMQV VVSRSGPSTP HVNFL LDSH PVSPEVIVEH TLNQNGYTLV ITGKKITKIP LNGLGCRHFQ SCSQCLSAPP FVQCGWCHDK CVRSEECLSG TWTQQI CLP AIYKVFPNSA PLEGGTRLTI CGWDFGFRRN NKFDLKKTRV LLGNESCTLT LSESTMNTLK CTVGPAMNKH FNMSIII SN GHGTTQYSTF SYVDPVITSI SPKYGPMAGG TLLTLTGNYL NSGNSRHISI GGKTCTLKSV SNSILECYTP AQTISTEF A VKLKIDLANR ETSIFSYRED PIVYEIHPTK SFISGGSTIT GVGKNLNSVS VPRMVINVHE AGRNFTVACQ HRSNSEIIC CTTPSLQQLN LQLPLKTKAF FMLDGILSKY FDLIYVHNPV FKPFEKPVMI SMGNENVLEI KGNDIDPEAV KGEVLKVGNK SCENIHLHS EAVLCTVPND LLKLNSELNI EWKQAISSTV LGKVIVQPDQ NFTGLIAGVV SISTALLLLL GFFLWLKKRK Q IKDLGSEL VRYDARVHTP HLDRLVSARS VSPTTEMVSN ESVDYRATFP EDQFPNSSQN GSCRQVQYPL TDMSPILTSG DS DISSPLL QNTVHIDLSA LNPELVQAVQ HVVIGPSSLI VHFNEVIGRG HFGCVYHGTL LDNDGKKIHC AVKSLNRITD IGE VSQFLT EGIIMKDFSH PNVLSLLGIC LRSEGSPLVV LPYMKHGDLR NFIRNETHNP TVKDLIGFGL QVAKGMKYLA SKKF VHRDL AARNCMLDEK FTVKVADFGL ARDMYDKEYY SVHNKTGAKL PVKWMALESL QTQKFTTKSD VWSFGVLLWE LMTRG APPY PDVNTFDITV YLLQGRRLLQ PEYCPDPLYE VMLKCWHPKA EMRPSFSELV SRISAIFSTF IGEHYVHVNA TYVNVK CVA PYPSLLSSED NADDEVDTRP ASFWETS |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE |
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 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 25787 |
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Initial angle assignment | Type: PROJECTION MATCHING / Software - Name: RELION |
Final angle assignment | Type: PROJECTION MATCHING / Software - Name: RELION |
Final 3D classification | Software - Name: RELION |