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- EMDB-52489: Cryo-EM structure of acylaminoacyl peptidase (AAP) in covalent co... -

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Basic information

Entry
Database: EMDB / ID: EMD-52489
TitleCryo-EM structure of acylaminoacyl peptidase (AAP) in covalent complex with inhibitor AEBSF
Map data
Sample
  • Complex: Tetrameric structure of acylaminoacyl-peptidase (AAP) in covalent complex with AES hydrolysed from AEBSF
    • Protein or peptide: Acylamino-acid-releasing enzyme
  • Ligand: 4-(2-AMINOETHYL)BENZENESULFONYL FLUORIDE
Keywordsinhibitor / covalent / serine-protease / acylpeptide hydrolase / APEH / OPH / acylaminoacyl peptidase / sulphonate / HYDROLASE
Function / homology
Function and homology information


acylaminoacyl-peptidase / omega peptidase activity / serine-type endopeptidase activity / proteolysis / cytoplasm
Similarity search - Function
Acylamino-acid-releasing enzyme, N-terminal domain / Acylamino-acid-releasing enzyme, N-terminal domain / Prolyl endopeptidase family serine active site. / Peptidase S9, serine active site / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Six-bladed beta-propeller, TolB-like / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Acylamino-acid-releasing enzyme
Similarity search - Component
Biological speciesSus scrofa (pig)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsKiss-Szeman AJ / Menyhard DK / Harmat V / Perczel A
Funding support Hungary, European Union, 3 items
OrganizationGrant numberCountry
National Research Development and Innovation Office (NKFIH)2018-1.2.1-NKP-2018-00005 Hungary
European Union (EU)RRF-2.3.1-21-2022-00015European Union
National Research Development and Innovation Office (NKFIH)2020-1.1.6-JOVO-2021-00010 Hungary
CitationJournal: Protein Sci / Year: 2025
Title: Ligand binding Pro-miscuity of acylpeptide hydrolase, structural analysis of a detoxifying serine hydrolase.
Authors: Anna J Kiss-Szemán / Luca Takács / Imre Jákli / Zoltán Bánóczi / Naoki Hosogi / Daouda A K Traore / Veronika Harmat / András Perczel / Dóra K Menyhárd /
Abstract: Acylpeptide hydrolase (APEH) or acylaminoacyl-peptidase (AAP) is a serine hydrolase that regulates protein metabolism. It can also bind to and process unusual substrates, acting as a detoxifier. To ...Acylpeptide hydrolase (APEH) or acylaminoacyl-peptidase (AAP) is a serine hydrolase that regulates protein metabolism. It can also bind to and process unusual substrates, acting as a detoxifier. To better understand its promiscuous specificity, we determined the cryo-EM structures of mammalian APEH complexed with classical serine protease partners: a chloromethyl-ketone (CMK) inhibitor, an organophosphate (OP) pesticide (dichlorvos), and benzenesulfonyl-fluoride. Since CMK derivatives of N-acetylated peptides were suggested to induce apoptosis by inhibiting APEH, while OP complexes may serve as biomarkers of OP exposure and are linked to cognitive enhancement, these complexes carry physiological significance. We identified a unique strand-breaker Pro residue in the hydrolase domain, which relaxes the active site into a partially inactivated but more spacious conformation, transforming the classical serine protease apparatus into a versatile yet potent hydrolysis center with broad specificity, distinguishing the mammalian enzyme not only from other APEHs but also from serine α/β hydrolases sharing essentially the same fold.
History
DepositionJan 8, 2025-
Header (metadata) releaseOct 22, 2025-
Map releaseOct 22, 2025-
UpdateOct 22, 2025-
Current statusOct 22, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52489.png

Downloads & links

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Map

FileDownload / File: emd_52489.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 400 pix.
= 300. Å		0.75 Å/pix.
x 400 pix.
= 300. Å		0.75 Å/pix.
x 400 pix.
= 300. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.75 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0581
Minimum - Maximum-0.14680932 - 0.38152575
Average (Standard dev.)0.00088984444 (±0.0131655885)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 300.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_52489_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_52489_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Tetrameric structure of acylaminoacyl-peptidase (AAP) in covalent...

EntireName: Tetrameric structure of acylaminoacyl-peptidase (AAP) in covalent complex with AES hydrolysed from AEBSF
Components
  • Complex: Tetrameric structure of acylaminoacyl-peptidase (AAP) in covalent complex with AES hydrolysed from AEBSF
    • Protein or peptide: Acylamino-acid-releasing enzyme
  • Ligand: 4-(2-AMINOETHYL)BENZENESULFONYL FLUORIDE

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Supramolecule #1: Tetrameric structure of acylaminoacyl-peptidase (AAP) in covalent...

SupramoleculeName: Tetrameric structure of acylaminoacyl-peptidase (AAP) in covalent complex with AES hydrolysed from AEBSF
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Sus scrofa (pig)

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Macromolecule #1: Acylamino-acid-releasing enzyme

MacromoleculeName: Acylamino-acid-releasing enzyme / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: acylaminoacyl-peptidase
Source (natural)Organism: Sus scrofa (pig)
Molecular weightTheoretical: 81.324391 KDa
SequenceString: MERQVLLSEP EEAAALYRGL SRQPALSAAC LGPEVTTQYG GRYRTVHTEW TQRDLERMEN IRFCRQYLVF HDGDSVVFAG PAGNSVETR GELLSRESPS GTMKAVLRKA GGTGTAEEKQ FLEVWEKNRK LKSFNLSALE KHGPVYEDDC FGCLSWSHSE T HLLYVADK ...String:
MERQVLLSEP EEAAALYRGL SRQPALSAAC LGPEVTTQYG GRYRTVHTEW TQRDLERMEN IRFCRQYLVF HDGDSVVFAG PAGNSVETR GELLSRESPS GTMKAVLRKA GGTGTAEEKQ FLEVWEKNRK LKSFNLSALE KHGPVYEDDC FGCLSWSHSE T HLLYVADK KRPKAESFFQ TKALDVTGSD DEMARTKKPD QAIKGDQFLF YEDWGENMVS KSTPVLCVLD IESGNISVLE GV PESVSPG QAFWAPGDTG VVFVGWWHEP FRLGIRFCTN RRSALYYVDL TGGKCELLSD ESVAVTSPRL SPDQCRIVYL RFP SLVPHQ QCGQLCLYDW YTRVTSVVVD IVPRQLGEDF SGIYCSLLPL GCWSADSQRV VFDSPQRSRQ DLFAVDTQMG SVTS LTAGG SGGSWKLLTI DRDLMVVQFS TPSVPPSLKV GFLPPAGKEQ AVSWVSLEEA EPFPDISWSI RVLQPPPQQE HVQYA GLDF EAILLQPSNS PEKTQVPMVV MPHGGPHSSF VTAWMLFPAM LCKMGFAVLL VNYRGSTGFG QDSILSLPGN VGHQDV KDV QFAVEQVLQE EHFDAGRVAL MGGSHGGFLS CHLIGQYPET YSACVVRNPV INIASMMGST DIPDWCMVEA GFSYSSD CL PDLSVWAAML DKSPIKYAPQ VKTPLLLMLG QEDRRVPFKQ GMEYYRVLKA RNVPVRLLLY PKSTHALSEV EVESDSFM N AVLWLCTHLG S

UniProtKB: Acylamino-acid-releasing enzyme

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Macromolecule #2: 4-(2-AMINOETHYL)BENZENESULFONYL FLUORIDE

MacromoleculeName: 4-(2-AMINOETHYL)BENZENESULFONYL FLUORIDE / type: ligand / ID: 2 / Number of copies: 4 / Formula: AES
Molecular weightTheoretical: 203.234 Da
Chemical component information

ChemComp-AES:
4-(2-AMINOETHYL)BENZENESULFONYL FLUORIDE

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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

Concentration0.5 mg/mL
BufferpH: 7.5 / Component - Concentration: 10.0 mM / Component - Formula: TRIS / Component - Name: TRIS
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Average electron dose: 12.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 165000
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: PDB ENTRY
PDB model - PDB ID:

7px8

Final reconstructionNumber classes used: 10 / Applied symmetry - Point group: D2 (2x2 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 169418
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final 3D classificationNumber classes: 10 / Software - Name: cryoSPARC (ver. 4.6.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7px8


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9hxq:
Cryo-EM structure of acylaminoacyl peptidase (AAP) in covalent complex with inhibitor AEBSF

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