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- EMDB-23920: Cryo-EM structure of 1:1 c-MET I/HGF I complex after focused 3D r... -

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Basic information

Entry
Database: EMDB / ID: EMD-23920
TitleCryo-EM structure of 1:1 c-MET I/HGF I complex after focused 3D refinement of holo-complex
Map dataCryo-EM map of 1:1 c-MET I/HGF I complex after focused 3D refinement of holo-complex
Sample
  • Complex: 1:1 c-MET I/HGF I complex
    • Protein or peptide: Hepatocyte growth factor
    • Protein or peptide: Hepatocyte growth factor receptorC-Met
Function / homology
Function and homology information


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 / positive regulation of endothelial cell chemotaxis / MET receptor recycling / pancreas development / MET activates PTPN11 / MET activates RAP1 and RAC1 / Sema4D mediated inhibition of cell attachment and migration / myoblast proliferation / MET activates PI3K/AKT signaling / negative regulation of stress fiber assembly / negative regulation of Rho protein signal transduction / MET activates PTK2 signaling / positive regulation of DNA biosynthetic process / cellular response to hepatocyte growth factor stimulus / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of thrombin-activated receptor signaling pathway / negative regulation of release of cytochrome c from mitochondria / chemoattractant activity / negative regulation of interleukin-6 production / semaphorin-plexin signaling pathway / positive regulation of interleukin-10 production / epithelial to mesenchymal transition / establishment of skin barrier / positive regulation of osteoblast differentiation / MET activates RAS signaling / negative regulation of peptidyl-serine phosphorylation / 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 / cell chemotaxis / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / 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 / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of peptidyl-tyrosine phosphorylation / 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 / positive regulation of MAPK cascade / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of cell migration / positive regulation of protein phosphorylation / 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 / membrane / identical protein binding / plasma membrane
Similarity search - Function
Hepatocyte growth factor / Hepatocyte growth factor/Macrophage stimulatory protein / divergent subfamily of APPLE domains / Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain ...Hepatocyte growth factor / Hepatocyte growth factor/Macrophage stimulatory protein / divergent subfamily of APPLE domains / Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / IPT/TIG domain / ig-like, plexins, transcription factors / PSI domain / domain found in Plexins, Semaphorins and Integrins / IPT domain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Kringle-like fold / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Immunoglobulin E-set / Trypsin / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Peptidase S1, PA clan, chymotrypsin-like fold / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Peptidase S1, PA clan / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Hepatocyte growth factor receptor / Hepatocyte growth factor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsUchikawa E / Chen ZM / Xiao GY / Zhang XW / Bai XC
CitationJournal: Nat Commun / Year: 2021
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
DepositionMay 1, 2021-
Header (metadata) releaseJun 9, 2021-
Map releaseJun 9, 2021-
UpdateJul 28, 2021-
Current statusJul 28, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mo8
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23920.png

Downloads & links

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Map

FileDownload / File: emd_23920.map.gz / Format: CCP4 / Size: 75.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of 1:1 c-MET I/HGF I complex after focused 3D refinement of holo-complex
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.016 / Movie #1: 0.016
Minimum - Maximum-0.017888956 - 0.044926252
Average (Standard dev.)9.532235e-05 (±0.001854064)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions270270270
Spacing270270270
CellA=B=C: 291.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z270270270
origin x/y/z0.0000.0000.000
length x/y/z291.600291.600291.600
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ192192192
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS270270270
D min/max/mean-0.0180.0450.000

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Supplemental data

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Sample components

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Entire : 1:1 c-MET I/HGF I complex

EntireName: 1:1 c-MET I/HGF I complex
Components
  • Complex: 1:1 c-MET I/HGF I complex
    • Protein or peptide: Hepatocyte growth factor
    • Protein or peptide: Hepatocyte growth factor receptorC-Met

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Supramolecule #1: 1:1 c-MET I/HGF I complex

SupramoleculeName: 1:1 c-MET I/HGF I complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Hepatocyte growth factor

MacromoleculeName: Hepatocyte growth factor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 83.249828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: Hepatocyte growth factor receptor

MacromoleculeName: Hepatocyte growth factor receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 155.720625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 25787

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