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- EMDB-32716: Structure of Active-mutEP -

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Basic information

Entry
Database: EMDB / ID: EMD-32716
TitleStructure of Active-mutEP
Map data
Sample
  • Complex: active-mutEP
    • Protein or peptide: Enteropeptidase non-catalytic heavy chain
    • Protein or peptide: Enteropeptidase catalytic light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsCOMPLEX / MEMBRANE PROTEIN
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) / SEA domain profile. / SEA domain / SEA domain / SRCR domain profile. ...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) / SEA domain profile. / SEA domain / SEA domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR 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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / 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
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsYang XL / Ding ZY
Funding support1 items
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, 2022-
Header (metadata) releaseOct 26, 2022-
Map releaseOct 26, 2022-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32716.png

Downloads & links

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Map

FileDownload / File: emd_32716.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 256 pix.
= 267.776 Å		1.05 Å/pix.
x 256 pix.
= 267.776 Å		1.05 Å/pix.
x 256 pix.
= 267.776 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.046 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.201
Minimum - Maximum-0.5266392 - 1.0492266
Average (Standard dev.)-0.00017192123 (±0.016579269)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 267.776 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : active-mutEP

EntireName: active-mutEP
Components
  • Complex: active-mutEP
    • Protein or peptide: Enteropeptidase non-catalytic heavy chain
    • Protein or peptide: Enteropeptidase catalytic light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: active-mutEP

SupramoleculeName: active-mutEP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Enteropeptidase non-catalytic heavy chain

MacromoleculeName: Enteropeptidase non-catalytic heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.703256 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: CGGPFELWEP NTTFSSTNFP NSYPNLAFCV WILNAQKGKN IQLHFQEFDL ENINDVVEIR DGEEADSLLL AVYTGPGPVK DVFSTTNRM TVLLITNDVL ARGGFKANFT TGYHLGIPEP CKADHFQCKN GECVPLVNLC DGHLHCEDGS DEADCVRFFN G TTNNNGLV ...String:
CGGPFELWEP NTTFSSTNFP NSYPNLAFCV WILNAQKGKN IQLHFQEFDL ENINDVVEIR DGEEADSLLL AVYTGPGPVK DVFSTTNRM TVLLITNDVL ARGGFKANFT TGYHLGIPEP CKADHFQCKN GECVPLVNLC DGHLHCEDGS DEADCVRFFN G TTNNNGLV RFRIQSIWHT ACAENWTTQI SNDVCQLLGL GSGNSSKPIF PTDGGPFVKL NTAPDGHLIL TPSQQCLQDS LI RLQCNHK SCGKKLAAQD ITPK

UniProtKB: Enteropeptidase

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Macromolecule #2: Enteropeptidase catalytic light chain

MacromoleculeName: Enteropeptidase catalytic light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.15068 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: IVGGSNAKEG AWPWVVGLYY GGRLLCGASL VSSDWLVSAA ACVYGRNLEP SKWTAILGLH MKSNLTSPQT VPRLIDEIVI NPHYNRRRK DNAIAMMHLE FKVNYTDYIQ PICLPEENQV FPPGRNCSIA GWGTVVYQGT TANILQEADV PLLSNERCQQ Q MPEYNITE ...String:
IVGGSNAKEG AWPWVVGLYY GGRLLCGASL VSSDWLVSAA ACVYGRNLEP SKWTAILGLH MKSNLTSPQT VPRLIDEIVI NPHYNRRRK DNAIAMMHLE FKVNYTDYIQ PICLPEENQV FPPGRNCSIA GWGTVVYQGT TANILQEADV PLLSNERCQQ Q MPEYNITE NMICAGYEEG GIDSCQGDAG GPLMCQENNR WFLAGVTSFG YKCALPNRPG VYARVSRFTE WIQSFLH

UniProtKB: Enteropeptidase

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 9 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 7.6
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.4 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 156344
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: ANGULAR RECONSTITUTION

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