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- EMDB-58529: CryoEM structure of a catalytically inactive CXC Chemokine-degrad... -

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Basic information

Entry
Database: EMDB / ID: EMD-58529
TitleCryoEM structure of a catalytically inactive CXC Chemokine-degrading protease SpyCEP from Streptococcus pyogenes complexed with an anti-N-terminal monoclonal antibody
Map data
Sample
  • Complex: SpyCEP complexed with 10B6C10
    • Protein or peptide: Streptococcus pyogenes cell envelope protease (SpyCEP) N-terminal D151A
    • Protein or peptide: Streptococcus pyogenes cell envelope protease (SpyCEP) C-terminal S617A
    • Protein or peptide: Anti-N-terminal monoclonal antibody (10B6C10) Light chain variable region
    • Protein or peptide: Anti-N-terminal monoclonal antibody (10B6C10) Heavy chain variable region
KeywordsBacterial / protease / complex / antibody / immune evasion / chemokine / PROTEIN BINDING
Biological speciesMus musculus (house mouse) / Streptococcus pyogenes (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.5 Å
AuthorsLau RJ / Wu GHY / Barritt JD / 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_58529.png

Downloads & links

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Map

FileDownload / File: emd_58529.map.gz / Format: CCP4 / Size: 155.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.16 Å/pix.
x 344 pix.
= 399.04 Å		1.16 Å/pix.
x 344 pix.
= 399.04 Å		1.16 Å/pix.
x 344 pix.
= 399.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.16 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.25459588 - 0.9041056
Average (Standard dev.)0.00009264415 (±0.020034187)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions344344344
Spacing344344344
CellA=B=C: 399.03998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_58529_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_58529_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : SpyCEP complexed with 10B6C10

EntireName: SpyCEP complexed with 10B6C10
Components
  • Complex: SpyCEP complexed with 10B6C10
    • Protein or peptide: Streptococcus pyogenes cell envelope protease (SpyCEP) N-terminal D151A
    • Protein or peptide: Streptococcus pyogenes cell envelope protease (SpyCEP) C-terminal S617A
    • Protein or peptide: Anti-N-terminal monoclonal antibody (10B6C10) Light chain variable region
    • Protein or peptide: Anti-N-terminal monoclonal antibody (10B6C10) Heavy chain variable region

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Supramolecule #1: SpyCEP complexed with 10B6C10

SupramoleculeName: SpyCEP complexed with 10B6C10 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: C1 symmetry
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 325 KDa

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Macromolecule #1: Streptococcus pyogenes cell envelope protease (SpyCEP) N-terminal...

MacromoleculeName: Streptococcus pyogenes cell envelope protease (SpyCEP) N-terminal D151A
type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Streptococcus pyogenes (bacteria)
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSHHHHHH ADELSTMSEP TITNHAQQQA QHLTNTELSS AESKSQDTSQ ITLKTNREKE QSQDLVSEPT TTELADTDAA SMANTGSDAT QKSASLPPVN TDVHDWVKTK GAWDKGYKGQ GKVVAVIATG IDPAHQSMRI SDVSTAKVKS KEDMLARQKA AGINYGSWIN ...String:
MGSSHHHHHH ADELSTMSEP TITNHAQQQA QHLTNTELSS AESKSQDTSQ ITLKTNREKE QSQDLVSEPT TTELADTDAA SMANTGSDAT QKSASLPPVN TDVHDWVKTK GAWDKGYKGQ GKVVAVIATG IDPAHQSMRI SDVSTAKVKS KEDMLARQKA AGINYGSWIN DKVVFAHNYV ENSDNIKENQ FEDFDEDWEN FEFDAEAEPK AIKKHKIYRP Q

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Macromolecule #2: Streptococcus pyogenes cell envelope protease (SpyCEP) C-terminal...

MacromoleculeName: Streptococcus pyogenes cell envelope protease (SpyCEP) C-terminal S617A
type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Streptococcus pyogenes (bacteria)
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSSTQAPK ETVIKTEETD GSHDIDWTQT DDDTKYESHG MHVTGIVAGN SKEAAATGER FLGIAPEAQV MFMRVFANDI MGSAESLFIK AIEDAVALGA DVINLSLGTA NGAQLSGSKP LMEAIEKAKK AGVSVVVAAG NERVYGSDHD DPLATNPDYG LVGSPSTGRT ...String:
MGSSSTQAPK ETVIKTEETD GSHDIDWTQT DDDTKYESHG MHVTGIVAGN SKEAAATGER FLGIAPEAQV MFMRVFANDI MGSAESLFIK AIEDAVALGA DVINLSLGTA NGAQLSGSKP LMEAIEKAKK AGVSVVVAAG NERVYGSDHD DPLATNPDYG LVGSPSTGRT PTSVAAINSK WVIQRLMTVK ELENRADLNH GKAIYSESVD FKDIKDSLGY DKSHQFAYVK ESTDAGYNAQ DVKGKIALIE RDPNKTYDEM IALAKKHGAL GVLIFNNKPG QSNRSMRLTA NGMGIPSAFI SHEFGKAMSQ LNGNGTGSLE FDSVVSKAPS QKGNEMNHFS NWGLTSDGYL KPDITAPGGD IYSTYNDNHY GSQTGTSMAS PQIAGASLLV KQYLEKTQPN LPKEKIADIV KNLLMSNAQI HVNPETKTTT SPRQQGAGLL NIDGAVTSGL YVTGKDNYGS ISLGNITDTM TFDVTVHNLS NKDKTLRYDT ELLTDHVDPQ KGRFTLTSHS LKTYQGGEVT VPANGKVTVR VTMDVSQFTK ELTKQMPNGY YLEGFVRFRD SQDDQLNRVN IPFVGFKGQF ENLAVAEESI YRLKSQGKTG FYFDESGPKD DIYVGKHFTG LVTLGSETNV STKTISDNGL HTLGTFKNAD GKFILEKNAQ GNPVLAISPN GDNNQNFAAF KGVFLRKYQG LKASVYHASD KEHKNPLWVS PESFKGDKNF NSDIRFAKST TLLGTAFSGK SLTGAELPDG HYHYVVSYYP DVVGAKRQEM TFDMILDRQK PVLSQATFDP ETNRFKPEPL KDRGLAGVRK DSAFYLERKD NKPYTVTIND SYKYVSVEDN KTFVERQADG SFILPLDKAK LGDFYYMVED FAGNVAIAKL GDHLPQTLGK TPIKLKLTDG NYQTKETLKD NLEMTQSDTG LVTNQAQLAV VHRNQPQSQL TKMNQDFFIS PNEDGNKDFV AFKGLKNNVY NDLTVNVYAK DDHQKQTPIW SSQAGASVSA IESTAWYGIT ARGSKVMPGD YQYVVTYRDE HGKEHQKQYT ISVNDKKPMI TQGRFDTING VDHFTPDKTK ALGSSGIVRE EVFYLAKKNG RKFDVTEGKD GITVSDNKVY IPKNPDGSYT ISKRDGVTLS DYYYLVEDRA GNVSFATLRD LKAVGKDKAV VNFGLDLPVP EDKQIVNFTY LVRDADGKPI ENLEYYNNSG NSLILPYGKY TVELLTYDTN AAKLESDKIV SFTLSADNNF QQVTFKITML ATSQITAHFD HLLPEGSRVS LKTAQDQLIP LEQSLYVPKA YGKTVQEGTY EVVVSLPKGY RIEGNTKVNT LPNEVHELSL RLVKVGDASD STGDHKVMSK NNSQALTASA TPTKSTTSAT AKAALEHHHH HH

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Macromolecule #3: Anti-N-terminal monoclonal antibody (10B6C10) Light chain variabl...

MacromoleculeName: Anti-N-terminal monoclonal antibody (10B6C10) Light chain variable region
type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
SequenceString:
DAVMTQTPLS LPVSLGDQAS ISCRSSQSLE NSNGNTYLNW YLQKPGQSPQ LLIYRVSNRF SGVLDRFSGS GSGTDFTLKI SRVEAEDLGV YFCLQVTHVP LTFGAGTKLE LK

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Macromolecule #4: Anti-N-terminal monoclonal antibody (10B6C10) Heavy chain variabl...

MacromoleculeName: Anti-N-terminal monoclonal antibody (10B6C10) Heavy chain variable region
type: protein_or_peptide / ID: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
SequenceString:
EVKLVESGGG LVQPGGSLRL SCATSGFTFT DYYMSWVRQP PGKALEWLGF IRNKANGYTI EYSASVKGRF TISRDNSQSI LYLQMNTLRV EDSATYYCAR ALDYWGLGTT LTVSS

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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: 7
Component:
ConcentrationFormulaName
200.0 mMNaClsodium chloride
20.0 mMTris-HCLtris hydrochloride
0.03 %DDMn dodecyl beta D maltoside

Details: 20 mM Tris pH 7.0, 200 mM NaCl, 0.003% DDM
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: 1182 / Average electron dose: 50.0 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: 100000
Sample stageCooling holder cryogen: NITROGEN

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Image processing

Particle selectionNumber selected: 223716
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 5.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 44200
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementOverall B value: 102.9

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