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- PDB-7wr7: Structure of Inhibited-EP -

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Basic information

Entry
Database: PDB / ID: 7wr7
TitleStructure of Inhibited-EP
Components
  • Enteropeptidase catalytic light chain
  • Enteropeptidase non-catalytic heavy chain
KeywordsMEMBRANE PROTEIN / COMPLEX
Function / homology
Function and homology information


enteropeptidase / brush border / serine-type endopeptidase activity / proteolysis / membrane
Similarity search - Function
Peptidase S1A, enteropeptidase / Scavenger receptor cysteine-rich domain / Domain found in sea urchin sperm protein, enterokinase, agrin / MAM domain signature. / SEA domain superfamily / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / SRCR domain / SRCR domain profile. / SRCR-like domain / SRCR-like domain superfamily ...Peptidase S1A, enteropeptidase / Scavenger receptor cysteine-rich domain / Domain found in sea urchin sperm protein, enterokinase, agrin / MAM domain signature. / SEA domain superfamily / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / SRCR domain / SRCR domain profile. / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SEA domain profile. / SEA domain / SEA domain / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Concanavalin A-like lectin/glucanase domain superfamily / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
4-carbamimidamidobenzoic acid / Enteropeptidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsYang, X.L. / Ding, Z.Y. / Huang, H.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2022
Title: Cryo-EM structures reveal the activation and substrate recognition mechanism of human enteropeptidase.
Authors: Xiaoli Yang / Zhanyu Ding / Lisi Peng / Qiuyue Song / Deyu Zhang / Fang Cui / Chuanchao Xia / Keliang Li / Hua Yin / Shiyu Li / Zhaoshen Li / Haojie Huang /
Abstract: Enteropeptidase (EP) initiates intestinal digestion by proteolytically processing trypsinogen, generating catalytically active trypsin. EP dysfunction causes a series of pancreatic diseases including ...Enteropeptidase (EP) initiates intestinal digestion by proteolytically processing trypsinogen, generating catalytically active trypsin. EP dysfunction causes a series of pancreatic diseases including acute necrotizing pancreatitis. However, the molecular mechanisms of EP activation and substrate recognition remain elusive, due to the lack of structural information on the EP heavy chain. Here, we report cryo-EM structures of human EP in inactive, active, and substrate-bound states at resolutions from 2.7 to 4.9 Å. The EP heavy chain was observed to clamp the light chain with CUB2 domain for substrate recognition. The EP light chain N-terminus induced a rearrangement of surface-loops from inactive to active conformations, resulting in activated EP. The heavy chain then served as a hinge for light-chain conformational changes to recruit and subsequently cleave substrate. Our study provides structural insights into rearrangements of EP surface-loops and heavy chain dynamics in the EP catalytic cycle, advancing our understanding of EP-associated pancreatitis.
History
DepositionJan 26, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 26, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2022Group: 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
Revision 1.2Oct 30, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Enteropeptidase non-catalytic heavy chain
B: Enteropeptidase catalytic light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,15112
Polymers54,9812
Non-polymers2,17010
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Enteropeptidase non-catalytic heavy chain


Mass: 28703.256 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMPRSS15, ENTK, PRSS7 / Production host: Homo sapiens (human) / References: UniProt: P98073
#2: Protein Enteropeptidase catalytic light chain


Mass: 26277.760 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMPRSS15, ENTK, PRSS7 / Production host: Homo sapiens (human) / References: UniProt: P98073
#3: 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.: 9 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
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
#4: Chemical ChemComp-GBS / 4-carbamimidamidobenzoic acid / Nafamostat, bound form


Mass: 179.176 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H9N3O2 / Feature type: SUBJECT OF INVESTIGATION
Comment: anticancer, anticoagulant, antivirus, protease inhibitor*YM
Has ligand of interestY
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: inhibited-EP / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.6
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 FIELD / Nominal defocus max: 3400 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 343205 / Symmetry type: POINT

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