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- EMDB-58555: CryoEM structure of a catalytically inactive CXC Chemokine-degrad... -

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Basic information

Entry
Database: EMDB / ID: EMD-58555
TitleCryoEM structure of a catalytically inactive CXC Chemokine-degrading protease SpyCEP from Streptococcus pyogenes complexed with an anti-PA-domain monoclonal antibody
Map data
Sample
  • Complex: SpyCEP complexed with 3F2G10
    • Protein or peptide: Cell envelope proteinase A
    • Protein or peptide: Cell envelope proteinase A
    • Protein or peptide: Anti-PA-domain monoclonal antibody (3F2G10) Heavy chain variable region
    • Protein or peptide: Anti-PA-domain monoclonal antibody (3F2G10) Light chain variable region
KeywordsBacterial / protease / complex / antibody / immune evasion / chemokine / PROTEIN BINDING
Function / homology
Function and homology information


serine-type endopeptidase activity / proteolysis / membrane
Similarity search - Function
Fn3-like domain / C5a peptidase-like domain / Fn3-like domain / : / PA domain / PA domain superfamily / PA domain / YSIRK type signal peptide / YSIRK Gram-positive signal peptide / Peptidase S8, subtilisin, His-active site ...Fn3-like domain / C5a peptidase-like domain / Fn3-like domain / : / PA domain / PA domain superfamily / PA domain / YSIRK type signal peptide / YSIRK Gram-positive signal peptide / Peptidase S8, subtilisin, His-active site / Serine proteases, subtilase family, histidine active site. / Serine proteases, subtilase family, aspartic acid active site. / Peptidase S8, subtilisin, Asp-active site / Serine proteases, subtilase family, serine active site. / Peptidase S8, subtilisin, Ser-active site / Gram-positive cocci surface proteins LPxTG motif profile. / LPXTG cell wall anchor domain / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / Immunoglobulin-like fold
Similarity search - Domain/homology
Cell envelope proteinase A
Similarity search - Component
Biological speciesStreptococcus pyogenes (bacteria) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsLau RJ / Barritt JD / Wu GHY / Huemer CB / Matthews S
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)UKRI682 United Kingdom
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: SpyCEP dismantles neutrophil immunity via disorder-driven chemokine remodeling and GAG targeting.
Authors: Rikin J Lau / Sean P Giblin / Andra Sugar / Antonio Di Maio / Giulio Tassini / Kristin Huse / Dror Chorev / Yuan Chen / Grace Ho-Yan Wu / Camilla Berg Huemer / Seung Yon Kim / Jayden ...Authors: Rikin J Lau / Sean P Giblin / Andra Sugar / Antonio Di Maio / Giulio Tassini / Kristin Huse / Dror Chorev / Yuan Chen / Grace Ho-Yan Wu / Camilla Berg Huemer / Seung Yon Kim / Jayden Matthews / Bel Muloud / Lu Chen / Sophie McKenna / Yingqi Xu / Luisa Massai / Chiara Muzzi / Xhenti Ferhati / Francesca Necchi / Danilo Gomes Moriel / Ten Feizi / Yan Liu / James E Pease / Shiranee Sriskandan / Steve Matthews /
Abstract: (Group A ) employs sophisticated virulence strategies to evade human immunity, including secretion of the cell envelope protease SpyCEP, which cleaves and inactivates key neutrophil-attracting ... (Group A ) employs sophisticated virulence strategies to evade human immunity, including secretion of the cell envelope protease SpyCEP, which cleaves and inactivates key neutrophil-attracting chemokines such as CXCL8. Here, we integrate cryo-electron microscopy, NMR spectroscopy, and native mass spectrometry to investigate how SpyCEP disrupts CXCL8 function. We demonstrate that a disordered aromatic and acidic region within the cleaved autocatalytic maturation loop (CAML) of SpyCEP mimics receptor N-domains and binds an allosteric site on CXCL8. The resulting interaction forms a dynamic fuzzy complex and is coupled to dimer dissociation, consistent with enhanced access to the cleavage site. This disorder-mediated substrate engagement differs from classical protease mechanisms that rely on rigid recognition interfaces. Additionally, glycan microarray and NMR analyses show that the CAML region mediates glycosaminoglycan (GAG) binding, suggesting a means for SpyCEP to maximize encounters with GAG-enriched CXCL8 reservoirs. Together, these findings provide a structural and biophysical framework for understanding how SpyCEP combines substrate engagement with GAG targeting to dismantle chemokine gradients and inhibit neutrophil recruitment. More broadly, this work highlights the role of intrinsic disorder in protease recognition and suggests avenues for anti-virulence therapies and vaccine strategies targeting SpyCEP.
History
DepositionJun 12, 2026-
Header (metadata) releaseJul 1, 2026-
Map releaseJul 1, 2026-
UpdateJul 22, 2026-
Current statusJul 22, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_58555.png

Downloads & links

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Map

FileDownload / File: emd_58555.map.gz / Format: CCP4 / Size: 476.8 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 500 pix.
= 375. Å		0.75 Å/pix.
x 500 pix.
= 375. Å		0.75 Å/pix.
x 500 pix.
= 375. 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: 0.05
Minimum - Maximum-0.12438007 - 0.28537354
Average (Standard dev.)-0.0002792762 (±0.004808477)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions500500500
Spacing500500500
CellA=B=C: 375.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_58555_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_58555_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 : SpyCEP complexed with 3F2G10

EntireName: SpyCEP complexed with 3F2G10
Components
  • Complex: SpyCEP complexed with 3F2G10
    • Protein or peptide: Cell envelope proteinase A
    • Protein or peptide: Cell envelope proteinase A
    • Protein or peptide: Anti-PA-domain monoclonal antibody (3F2G10) Heavy chain variable region
    • Protein or peptide: Anti-PA-domain monoclonal antibody (3F2G10) Light chain variable region

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Supramolecule #1: SpyCEP complexed with 3F2G10

SupramoleculeName: SpyCEP complexed with 3F2G10 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Streptococcus pyogenes (bacteria)
Molecular weightTheoretical: 325 KDa

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Macromolecule #1: Cell envelope proteinase A

MacromoleculeName: Cell envelope proteinase A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Streptococcus pyogenes (bacteria)
Molecular weightTheoretical: 24.609822 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSHHHHHH ADELSTMSEP TITNHAQQQA QHLTNTELSS AESKSQDTSQ ITLKTNREKE QSQDLVSEPT TTELADTDAA SMANTGSDA TQKSASLPPV NTDVHDWVKT KGAWDKGYKG QGKVVAVIAT GIDPAHQSMR ISDVSTAKVK SKEDMLARQK A AGINYGSW ...String:
MGSSHHHHHH ADELSTMSEP TITNHAQQQA QHLTNTELSS AESKSQDTSQ ITLKTNREKE QSQDLVSEPT TTELADTDAA SMANTGSDA TQKSASLPPV NTDVHDWVKT KGAWDKGYKG QGKVVAVIAT GIDPAHQSMR ISDVSTAKVK SKEDMLARQK A AGINYGSW INDKVVFAHN YVENSDNIKE NQFEDFDEDW ENFEFDAEAE PKAIKKHKIY RPQ

UniProtKB: Cell envelope proteinase A

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Macromolecule #2: Cell envelope proteinase A

MacromoleculeName: Cell envelope proteinase A / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Streptococcus pyogenes (bacteria)
Molecular weightTheoretical: 148.494438 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSSTQAPK ETVIKTEETD GSHDIDWTQT DDDTKYESHG MHVTGIVAGN SKEAAATGER FLGIAPEAQV MFMRVFANDI MGSAESLFI KAIEDAVALG ADVINLSLGT ANGAQLSGSK PLMEAIEKAK KAGVSVVVAA GNERVYGSDH DDPLATNPDY G LVGSPSTG ...String:
MGSSSTQAPK ETVIKTEETD GSHDIDWTQT DDDTKYESHG MHVTGIVAGN SKEAAATGER FLGIAPEAQV MFMRVFANDI MGSAESLFI KAIEDAVALG ADVINLSLGT ANGAQLSGSK PLMEAIEKAK KAGVSVVVAA GNERVYGSDH DDPLATNPDY G LVGSPSTG RTPTSVAAIN SKWVIQRLMT VKELENRADL NHGKAIYSES VDFKDIKDSL GYDKSHQFAY VKESTDAGYN AQ DVKGKIA LIERDPNKTY DEMIALAKKH GALGVLIFNN KPGQSNRSMR LTANGMGIPS AFISHEFGKA MSQLNGNGTG SLE FDSVVS KAPSQKGNEM NHFSNWGLTS DGYLKPDITA PGGDIYSTYN DNHYGSQTGT AMASPQIAGA SLLVKQYLEK TQPN LPKEK IADIVKNLLM SNAQIHVNPE TKTTTSPRQQ GAGLLNIDGA VTSGLYVTGK DNYGSISLGN ITDTMTFDVT VHNLS NKDK TLRYDTELLT DHVDPQKGRF TLTSHSLKTY QGGEVTVPAN GKVTVRVTMD VSQFTKELTK QMPNGYYLEG FVRFRD SQD DQLNRVNIPF VGFKGQFENL AVAEESIYRL KSQGKTGFYF DESGPKDDIY VGKHFTGLVT LGSETNVSTK TISDNGL HT LGTFKNADGK FILEKNAQGN PVLAISPNGD NNQNFAAFKG VFLRKYQGLK ASVYHASDKE HKNPLWVSPE SFKGDKNF N SDIRFAKSTT LLGTAFSGKS LTGAELPDGH YHYVVSYYPD VVGAKRQEMT FDMILDRQKP VLSQATFDPE TNRFKPEPL KDRGLAGVRK DSAFYLERKD NKPYTVTIND SYKYVSVEDN KTFVERQADG SFILPLDKAK LGDFYYMVED FAGNVAIAKL GDHLPQTLG KTPIKLKLTD GNYQTKETLK DNLEMTQSDT GLVTNQAQLA VVHRNQPQSQ LTKMNQDFFI SPNEDGNKDF V AFKGLKNN VYNDLTVNVY AKDDHQKQTP IWSSQAGASV SAIESTAWYG ITARGSKVMP GDYQYVVTYR DEHGKEHQKQ YT ISVNDKK PMITQGRFDT INGVDHFTPD KTKALGSSGI VREEVFYLAK KNGRKFDVTE GKDGITVSDN KVYIPKNPDG SYT ISKRDG VTLSDYYYLV EDRAGNVSFA TLRDLKAVGK DKAVVNFGLD LPVPEDKQIV NFTYLVRDAD GKPIENLEYY NNSG NSLIL PYGKYTVELL TYDTNAAKLE SDKIVSFTLS ADNNFQQVTF KITMLATSQI TAHFDHLLPE GSRVSLKTAQ DQLIP LEQS LYVPKAYGKT VQEGTYEVVV SLPKGYRIEG NTKVNTLPNE VHELSLRLVK VGDALEHHHH HH

UniProtKB: Cell envelope proteinase A

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Macromolecule #3: Anti-PA-domain monoclonal antibody (3F2G10) Heavy chain variable ...

MacromoleculeName: Anti-PA-domain monoclonal antibody (3F2G10) Heavy chain variable region
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.333943 KDa
SequenceString:
EVRLVESGGG LVKPGGSLKL SCAASGFTLN SYAMSWVRQT PEKRLEWVAS ISRGGSTFYP DDVRGRFTFS RDNARNILYL QMSSLRSED TAMYYCARGI LGNYGIFGAI DNWGQGTSVT VSS

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Macromolecule #4: Anti-PA-domain monoclonal antibody (3F2G10) Light chain variable ...

MacromoleculeName: Anti-PA-domain monoclonal antibody (3F2G10) Light chain variable region
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.324799 KDa
SequenceString:
DIVMTQSPSS LAMSVGQKVT MSCKSSQNLL NSSNQKNYLA WYQQKPGQSP KLLVFFASSR ESGVPDRFIG SGSGTDFTLT ISSVQAEDL ADYFCQQHSS IPFTFGSGTK LEMK

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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

Concentration1.625 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
200.0 mMNaClsodium chloride
20.0 mMTris-HCLtris hydrochloride

Details: 20 mM Tris pH 8.0, 200 mM NaCl
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 294.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 1959 / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 79000
Sample stageCooling holder cryogen: NITROGEN

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Image processing

Particle selectionNumber selected: 1351301
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: Alphafold 3 prediction of SpyCEP + 3F2G10
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 660420
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
DetailsFlexible fitting all performed in ISOLDE
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 129.9
Output model

PDB-31mr:
CryoEM structure of a catalytically inactive CXC Chemokine-degrading protease SpyCEP from Streptococcus pyogenes complexed with an anti-PA-domain monoclonal antibody

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