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- PDB-7mo8: Cryo-EM structure of 1:1 c-MET I/HGF I complex after focused 3D r... -

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Basic information

Entry
Database: PDB / ID: 7mo8
TitleCryo-EM structure of 1:1 c-MET I/HGF I complex after focused 3D refinement of holo-complex
Components
  • Hepatocyte growth factor receptorC-Met
  • Hepatocyte growth factor
KeywordsSIGNALING PROTEIN / c-MET / HGF / receptor tyrosine kinase
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsUchikawa, E. / Chen, Z.M. / Xiao, G.Y. / Zhang, X.W. / Bai, X.C.
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 9, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

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Assembly

Deposited unit
A: Hepatocyte growth factor
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)240,7213
Polymers238,9702
Non-polymers1,7501
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5980 Å2
ΔGint16 kcal/mol
Surface area57600 Å2

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Components

#1: Protein Hepatocyte growth factor / / Hepatopoietin-A / Scatter factor / SF


Mass: 83249.828 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HGF, HPTA / Production host: Homo sapiens (human) / References: UniProt: P14210
#2: Protein Hepatocyte growth factor receptor / C-Met / HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / ...HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / Tyrosine-protein kinase Met


Mass: 155720.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Homo sapiens (human)
References: UniProt: P08581, receptor protein-tyrosine kinase
#3: Polysaccharide 2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose- ...2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose


Type: oligosaccharide / Mass: 1750.427 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
WURCS=2.0/2,6,5/[a2122h-1a_1-5_2*NSO/3=O/3=O_6*OSO/3=O/3=O][a2121A-1a_1-5_2*OSO/3=O/3=O]/1-2-1-2-1-2/a4-b1_b4-c1_c4-d1_d4-e1_e4-f1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpN6SO3]{[(4+1)][a-L-IdopA2SO3]{[(4+1)][a-D-GlcpNSO36SO3]{[(4+1)][a-L-IdopA2SO3]{[(4+1)][a-D-XylpNSO3]{[(4+1)][a-L-4-deoxy-IdopA2SO3]{}}}}}}LINUCSPDB-CARE
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 1:1 c-MET I/HGF I complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
EM software
IDNameCategory
2SerialEMimage acquisition
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 25787 / Symmetry type: POINT
RefinementCross valid method: NONE

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