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- PDB-9p99: CryoEM structure of integrin alphaEbeta7 bound to E-cadherin -

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Basic information

Entry
Database: PDB / ID: 9p99
TitleCryoEM structure of integrin alphaEbeta7 bound to E-cadherin
Components
  • Cadherin-1
  • Integrin alpha-E
  • Integrin beta-7
KeywordsCELL ADHESION / aEb7 / gut adhesion / tissue residence / membrane receptor
Function / homology
Function and homology information


immune response in gut-associated lymphoid tissue / cell-matrix adhesion involved in ameboidal cell migration / integrin alpha4-beta7 complex / response to heparin / desmosome assembly / response to Gram-positive bacterium / pituitary gland development / gamma-catenin binding / Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition / negative regulation of axon extension ...immune response in gut-associated lymphoid tissue / cell-matrix adhesion involved in ameboidal cell migration / integrin alpha4-beta7 complex / response to heparin / desmosome assembly / response to Gram-positive bacterium / pituitary gland development / gamma-catenin binding / Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition / negative regulation of axon extension / desmosome / cellular response to indole-3-methanol / calcium-dependent cell-cell adhesion / flotillin complex / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / cell-cell adhesion mediated by cadherin / adherens junction organization / Formation of definitive endoderm / catenin complex / leukocyte tethering or rolling / Apoptotic cleavage of cell adhesion proteins / cell-cell junction assembly / Adherens junctions interactions / GTPase activating protein binding / integrin complex / ankyrin binding / heterotypic cell-cell adhesion / negative regulation of cell-cell adhesion / leukocyte migration / cellular response to lithium ion / cell adhesion mediated by integrin / apical junction complex / receptor clustering / homophilic cell-cell adhesion / lateral plasma membrane / Integrin cell surface interactions / RHO GTPases activate IQGAPs / T cell migration / synapse assembly / cell adhesion molecule binding / positive regulation of protein localization / Degradation of the extracellular matrix / Transcriptional and post-translational regulation of MITF-M expression and activity / substrate adhesion-dependent cell spreading / InlA-mediated entry of Listeria monocytogenes into host cells / protein tyrosine kinase binding / negative regulation of cell migration / cell-matrix adhesion / integrin-mediated signaling pathway / protein localization to plasma membrane / adherens junction / trans-Golgi network / cell-cell adhesion / beta-catenin binding / positive regulation of protein import into nucleus / response to toxic substance / cytoplasmic side of plasma membrane / integrin binding / cell morphogenesis / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / neuron projection development / cell junction / cell migration / lamellipodium / actin cytoskeleton / virus receptor activity / regulation of gene expression / receptor complex / postsynapse / cell adhesion / endosome / cadherin binding / response to xenobiotic stimulus / external side of plasma membrane / focal adhesion / calcium ion binding / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / glutamatergic synapse / cell surface / extracellular exosome / extracellular region / metal ion binding / identical protein binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Cadherin prodomain like / Cadherin prodomain / Cadherin prodomain like / Cadherin, Y-type LIR-motif / Cadherin, Y-type LIR-motif / Cadherin / Catenin binding domain superfamily / Integrin beta subunit, cytoplasmic domain / Cadherin conserved site / Integrin beta cytoplasmic domain ...Cadherin prodomain like / Cadherin prodomain / Cadherin prodomain like / Cadherin, Y-type LIR-motif / Cadherin, Y-type LIR-motif / Cadherin / Catenin binding domain superfamily / Integrin beta subunit, cytoplasmic domain / Cadherin conserved site / Integrin beta cytoplasmic domain / Cadherin domain signature. / Integrin_b_cyt / Cadherin repeats. / Integrin beta subunit, tail / Integrin beta tail domain superfamily / Integrin_B_tail / EGF-like domain, extracellular / EGF-like domain / Integrin alpha cytoplasmic region / Integrins beta chain EGF (I-EGF) domain profile. / Integrin beta subunit, VWA domain / Integrin beta subunit / Integrin beta N-terminal / Integrin beta chain VWA domain / Integrin plexin domain / Integrins beta chain EGF (I-EGF) domain signature. / Integrin beta subunits (N-terminal portion of extracellular region) / Cadherin domain / Cadherin-like / Cadherins domain profile. / Cadherin-like superfamily / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Integrins alpha chain signature. / Integrin alpha chain / Integrin alpha beta-propellor / : / Integrin alpha Ig-like domain 2 / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin alpha, N-terminal / Integrin domain superfamily / von Willebrand factor type A domain / PSI domain / domain found in Plexins, Semaphorins and Integrins / VWFA domain profile. / von Willebrand factor (vWF) type A domain / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2.
Similarity search - Domain/homology
: / Cadherin-1 / Integrin beta-7 / Integrin alpha-E
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.37 Å
AuthorsHollis, J.A. / Campbell, M.G.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM147414 United States
National Science Foundation (NSF, United States) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM008268 United States
CitationJournal: Sci Adv / Year: 2025
Title: Molecular exaptation by the integrin αI domain.
Authors: Jeremy A Hollis / Matthew C Chan / Harmit S Malik / Melody G Campbell /
Abstract: Integrins bind ligands between their alpha (α) and beta (β) subunits and transmit signals through conformational changes. Early in chordate evolution, some α subunits acquired an "inserted" (I) ...Integrins bind ligands between their alpha (α) and beta (β) subunits and transmit signals through conformational changes. Early in chordate evolution, some α subunits acquired an "inserted" (I) domain that expanded integrin's ligand-binding repertoire but obstructed the ancestral ligand pocket, seemingly blocking conventional integrin activation. Here, we compare cryo-electron microscopy structures of apo and ligand-bound states of the I domain-containing αEβ integrin and the I domain-lacking αβ integrin to illuminate how the I domain intrinsically mimics an extrinsic ligand to preserve integrin function. We trace the I domain's evolutionary origin to an ancestral collagen-collagen interaction domain, identifying an ancient molecular exaptation that facilitated integrin activation immediately upon I domain insertion. Our analyses reveal the evolutionary and biochemical basis of expanded cellular communication in vertebrates.
History
DepositionJun 24, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 24, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Integrin alpha-E
B: Integrin beta-7
C: Cadherin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)253,71616
Polymers251,1153
Non-polymers2,60113
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein Integrin alpha-E / HML-1 antigen / Integrin alpha-IEL / Mucosal lymphocyte 1 antigen


Mass: 129950.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Ectodomain / Source: (gene. exp.) Homo sapiens (human) / Gene: ITGAE / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P38570
#2: Protein Integrin beta-7 / Gut homing receptor beta subunit


Mass: 84538.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Ectodomain / Source: (gene. exp.) Homo sapiens (human) / Gene: ITGB7 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P26010
#3: Protein Cadherin-1 / CAM 120/80 / Epithelial cadherin / E-cadherin / Uvomorulin


Mass: 36625.715 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: First two domains of mature molecule / Source: (gene. exp.) Homo sapiens (human) / Gene: CDH1, CDHE, UVO / Production host: Escherichia coli (E. coli) / References: UniProt: P12830

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Sugars , 3 types, 6 molecules

#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 7 molecules

#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#8: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mn

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Details

Has ligand of interestN
Has protein modificationY

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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: Protein complex of integrin alphaEbeta7 bound to E-cadherin
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.4
SpecimenConc.: 0.15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.37 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 487193 / Symmetry type: POINT
RefinementHighest resolution: 3.37 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0059991
ELECTRON MICROSCOPYf_angle_d0.59513559
ELECTRON MICROSCOPYf_dihedral_angle_d7.5891581
ELECTRON MICROSCOPYf_chiral_restr0.0461547
ELECTRON MICROSCOPYf_plane_restr0.0051776

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