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- EMDB-71559: Cryo-EM structure of CCR6 bound by PF-07054894 and OXM2 -

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Basic information

Entry
Database: EMDB / ID: EMD-71559
TitleCryo-EM structure of CCR6 bound by PF-07054894 and OXM2
Map dataStructure of CCR6 bound by PF-07054894 and OXM2
Sample
  • Complex: Complex of Human CCR6/PF-07054894/OXM2 with anti-BRIL Fab and anti-BRIL Fab Nanobody
    • Protein or peptide: Human CCR6
    • Protein or peptide: anti-BRIL Fab Light chain
    • Protein or peptide: anti-BRIL Fab Nanobody
    • Protein or peptide: anti-BRIL Heavy chain
  • Ligand: N-{[(2R)-4-(bicyclo[1.1.1]pentan-1-yl)-5-oxomorpholin-2-yl]methyl}-1-[4-(trifluoromethyl)phenyl]cyclopropane-1-carboxamide
  • Ligand: 4-[(2-{[(R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]-3-hydroxy-N,N-dimethylpyridine-2-carboxamide
KeywordsGPCR / Complex / Antagonist / Membrane Protein
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsWasilko DJ / Wu H
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2025
Title: Discovery of PF-07054894, a Potent Squaramide-Based CCR6 Antagonist Displaying High CXCR2 Selectivity.
Authors: Mark E Schnute / Huixian Wu / John I Trujillo / Wei Li / David Jonathan Wasilko / Jennifer Alley / Eric P Arnold / Scott W Bagley / Gabriel Berstein / David C Blakemore / Mark W Bundesmann / ...Authors: Mark E Schnute / Huixian Wu / John I Trujillo / Wei Li / David Jonathan Wasilko / Jennifer Alley / Eric P Arnold / Scott W Bagley / Gabriel Berstein / David C Blakemore / Mark W Bundesmann / Gary M Chinigo / Chulho Choi / Robert Cooke / Kimberly Crouse / Alpay Dermenci / Theresa Dickinson / Andrew Flick / Richard K Frisbie / Carmen Garcia-Irizarry / Brian S Gerstenberger / David Hepworth / Neelu Kaila / Daniel W Kung / Daniel Lamb / Sophie Y Lavergne / David C Limburg / Shenping Liu / Vincent M Lombardo / Prolay K Mondal / James J Mousseau / Arjun Narayanan / Nootaree Niljianskul / Philippe Nuhant / Senliang Pan / Michael J Primiano / Mathieu Rappas / Daniel C Schmitt / Stefanus J Steyn / Ray Unwalla / Dipy Vasa / Michael L Vazquez / Fabien Vincent / Xiaojing Yang / Atli Thorarensen /
Abstract: The G protein-coupled receptor (GPCR) CCR6 mediates the migration of pathogenic immune cells to the site of inflammation in response to the chemokine CCL20. CCR6 is an attractive target for the ...The G protein-coupled receptor (GPCR) CCR6 mediates the migration of pathogenic immune cells to the site of inflammation in response to the chemokine CCL20. CCR6 is an attractive target for the treatment of chronic autoimmune disease as antagonism of the receptor is expected to block CCL20-mediated immune cell recruitment. High-throughput-screening identified a squaramide-based, allosteric antagonist of CCR6 that potently inhibited CCL20-mediated T cell chemotaxis, but it also inhibited CXCL1-mediated neutrophil chemotaxis through CXCR2 antagonism. Lead optimization achieved differentiation from CXCR2 through identification of a methyl substituent-dependent selectivity switch or "magic methyl for selectivity". The mechanism for this effect is rooted in different antagonist-induced ligand-receptor behaviors, insurmountable for CCR6 and surmountable for CXCR2. Herein, we report the discovery and preclinical evaluation of the CCR6 antagonist PF-07054894 () which has advanced to clinical trials as a first in class approach targeting the receptor.
History
DepositionJul 2, 2025-
Header (metadata) releaseOct 1, 2025-
Map releaseOct 1, 2025-
UpdateOct 8, 2025-
Current statusOct 8, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71559.png

Downloads & links

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Map

FileDownload / File: emd_71559.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of CCR6 bound by PF-07054894 and OXM2
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 400 pix.
= 293.2 Å		0.73 Å/pix.
x 400 pix.
= 293.2 Å		0.73 Å/pix.
x 400 pix.
= 293.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.733 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.089
Minimum - Maximum-0.48130736 - 0.76563287
Average (Standard dev.)-0.00016602871 (±0.010781503)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 293.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map B

Fileemd_71559_half_map_1.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_71559_half_map_2.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of Human CCR6/PF-07054894/OXM2 with anti-BRIL Fab and ant...

EntireName: Complex of Human CCR6/PF-07054894/OXM2 with anti-BRIL Fab and anti-BRIL Fab Nanobody
Components
  • Complex: Complex of Human CCR6/PF-07054894/OXM2 with anti-BRIL Fab and anti-BRIL Fab Nanobody
    • Protein or peptide: Human CCR6
    • Protein or peptide: anti-BRIL Fab Light chain
    • Protein or peptide: anti-BRIL Fab Nanobody
    • Protein or peptide: anti-BRIL Heavy chain
  • Ligand: N-{[(2R)-4-(bicyclo[1.1.1]pentan-1-yl)-5-oxomorpholin-2-yl]methyl}-1-[4-(trifluoromethyl)phenyl]cyclopropane-1-carboxamide
  • Ligand: 4-[(2-{[(R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]-3-hydroxy-N,N-dimethylpyridine-2-carboxamide

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Supramolecule #1: Complex of Human CCR6/PF-07054894/OXM2 with anti-BRIL Fab and ant...

SupramoleculeName: Complex of Human CCR6/PF-07054894/OXM2 with anti-BRIL Fab and anti-BRIL Fab Nanobody
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Human CCR6

MacromoleculeName: Human CCR6 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.62302 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTSV DSEMLLCSLQ EVRQFSRAFV PIAYSLICVF GLLGNILVV ITFAFYKKAR SMTDVYLANM AIADILFALT LPFWAVSHAT GAWVFSNATC KLLKGIYAIN FNCGMWLLTC I AMDRYIAI ...String:
MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTSV DSEMLLCSLQ EVRQFSRAFV PIAYSLICVF GLLGNILVV ITFAFYKKAR SMTDVYLANM AIADILFALT LPFWAVSHAT GAWVFSNATC KLLKGIYAIN FNCGMWLLTC I AMDRYIAI VQATKSFRLR SATLPRSKII CLVVWGLSVI ISSSTFVFNQ KYNTQGSDVC EPKYQTVSEP IRWKLLMLGL EL LFGFFIP LMFMIFCYTA IVKTLRRQLA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDAQ KATPPKLEDK SPD SPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLERAR STLQKEVKAI RVIIAVVLVF LACQ IPHNM VLLVTAANLG KMNRSCQSEK LIAYTKTVTE VLAFLHCCLN PVLYAFIGQK FRNYFLKILK DLWCVRRKYK SSGFS

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Macromolecule #2: anti-BRIL Fab Light chain

MacromoleculeName: anti-BRIL Fab Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.343348 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGWSCIILFL VATATGVHSS DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGT DFTLTISSLQ PEDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN F YPREAKVQ ...String:
MGWSCIILFL VATATGVHSS DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGT DFTLTISSLQ PEDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN F YPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRG

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Macromolecule #3: anti-BRIL Fab Nanobody

MacromoleculeName: anti-BRIL Fab Nanobody / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 15.755214 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MGHHHHHHHH HHENLYFQGS QVQLQESGGG LVQPGGSLRL SCAASGRTIS RYAMSWFRQA PGKEREFVAV ARRSGDGAFY ADSVQGRFT VSRDDAKNTV YLQMNSLKPE DTAVYYCAID SDTFYSGSYD YWGQGTQVTV SS

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Macromolecule #4: anti-BRIL Heavy chain

MacromoleculeName: anti-BRIL Heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.832098 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGWSCIILFL VATATGVHSE ISEVQLVESG GGLVQPGGSL RLSCAASGFN VVDFSLHWVR QAPGKGLEWV AYISSSSGST SYADSVKGR FTISADTSKN TAYLQMNSLR AEDTAVYYCA RWGYWPGEPW WKAFDYWGQG TLVTVSSAST KGPSVFPLAP S SKSTSGGT ...String:
MGWSCIILFL VATATGVHSE ISEVQLVESG GGLVQPGGSL RLSCAASGFN VVDFSLHWVR QAPGKGLEWV AYISSSSGST SYADSVKGR FTISADTSKN TAYLQMNSLR AEDTAVYYCA RWGYWPGEPW WKAFDYWGQG TLVTVSSAST KGPSVFPLAP S SKSTSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KV DKKVEPK SGGSENLYFQ GSHHHHHHHH HH

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Macromolecule #5: N-{[(2R)-4-(bicyclo[1.1.1]pentan-1-yl)-5-oxomorpholin-2-yl]methyl...

MacromoleculeName: N-{[(2R)-4-(bicyclo[1.1.1]pentan-1-yl)-5-oxomorpholin-2-yl]methyl}-1-[4-(trifluoromethyl)phenyl]cyclopropane-1-carboxamide
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1A1W
Molecular weightTheoretical: 408.414 Da

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Macromolecule #6: 4-[(2-{[(R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)me...

MacromoleculeName: 4-[(2-{[(R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]-3-hydroxy-N,N-dimethylpyridine-2-carboxamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1CH1
Molecular weightTheoretical: 466.533 Da

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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 mg/mL
BufferpH: 7.5
Details: 50 mM HEPES pH 7.5, 150 mM NaCl, 0.003% LMNG, 0.0003% CHS, 50 uM OXM2 and 50 uM of PF-07054894
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsCCR6-BRIL/Fab/Nb complex co-purified with PF-07054894 and OXM2

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 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: EMDB MAP
EMDB ID:

46533

Final reconstructionNumber classes used: 1 / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.1) / Number images used: 250839
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9d3e


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-9pee:
Cryo-EM structure of CCR6 bound by PF-07054894 and OXM2

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