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- EMDB-19011: Human PADI4 in complex with cyclic peptide PADI4_3 -

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Basic information

Entry
Database: EMDB / ID: EMD-19011
TitleHuman PADI4 in complex with cyclic peptide PADI4_3
Map data
Sample
  • Complex: Human PADI4 in complex with cyclic peptide PADI4_3
    • Protein or peptide: Protein-arginine deiminase type-4
    • Protein or peptide: Cyclic Peptide PADI4_3
  • Ligand: CALCIUM ION
KeywordsPADI4 / peptidyl arginine deiminase / Cyclic Peptide / CYTOSOLIC PROTEIN
Function / homology
Function and homology information


histone H3R2 arginine deiminase activity / histone H3R8 arginine deiminase activity / histone H3R17 arginine deiminase activity / histone arginine deiminase activity / histone H3R26 arginine deiminase activity / protein-arginine deiminase / protein-arginine deiminase activity / stem cell population maintenance / Chromatin modifying enzymes / post-translational protein modification ...histone H3R2 arginine deiminase activity / histone H3R8 arginine deiminase activity / histone H3R17 arginine deiminase activity / histone arginine deiminase activity / histone H3R26 arginine deiminase activity / protein-arginine deiminase / protein-arginine deiminase activity / stem cell population maintenance / Chromatin modifying enzymes / post-translational protein modification / protein modification process / nucleosome assembly / chromatin organization / chromatin remodeling / innate immune response / calcium ion binding / protein-containing complex / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Protein-arginine deiminase / Protein-arginine deiminase, C-terminal / Protein-arginine deiminase (PAD), N-terminal / Protein-arginine deiminase (PAD), central domain / Protein-arginine deiminase, central domain superfamily / PAD, N-terminal domain superfamily / Protein-arginine deiminase (PAD) / Protein-arginine deiminase (PAD) N-terminal domain / Protein-arginine deiminase (PAD) middle domain / Cupredoxin
Similarity search - Domain/homology
Protein-arginine deiminase type-4
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsBenton DJ / Bertran MT / Walport LJ
Funding support United Kingdom, 3 items
OrganizationGrant numberCountry
The Francis Crick InstituteCC2030 United Kingdom
The Francis Crick InstituteFC0010129 United Kingdom
The Francis Crick InstituteFC001134 United Kingdom
CitationJournal: Nat Commun / Year: 2024
Title: A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation.
Authors: M Teresa Bertran / Robert Walmsley / Thomas Cummings / Iker Valle Aramburu / Donald J Benton / Rocio Mora Molina / Jayalini Assalaarachchi / Maria Chasampalioti / Tessa Swanton / Dhira Joshi ...Authors: M Teresa Bertran / Robert Walmsley / Thomas Cummings / Iker Valle Aramburu / Donald J Benton / Rocio Mora Molina / Jayalini Assalaarachchi / Maria Chasampalioti / Tessa Swanton / Dhira Joshi / Stefania Federico / Hanneke Okkenhaug / Lu Yu / David Oxley / Simon Walker / Venizelos Papayannopoulos / Hiroaki Suga / Maria A Christophorou / Louise J Walport /
Abstract: Peptidylarginine deiminase IV (PADI4, PAD4) deregulation promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. PADI4 additionally mediates immune ...Peptidylarginine deiminase IV (PADI4, PAD4) deregulation promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. PADI4 additionally mediates immune responses and cellular reprogramming, although the full extent of its physiological roles is unexplored. Despite detailed molecular knowledge of PADI4 activation in vitro, we lack understanding of its regulation within cells, largely due to a lack of appropriate systems and tools. Here, we develop and apply a set of potent and selective PADI4 modulators. Using the mRNA-display-based RaPID system, we screen >10 cyclic peptides for high-affinity, conformation-selective binders. We report PADI4_3, a cell-active inhibitor specific for the active conformation of PADI4; PADI4_7, an inert binder, which we functionalise for the isolation and study of cellular PADI4; and PADI4_11, a cell-active PADI4 activator. Structural studies with PADI4_11 reveal an allosteric binding mode that may reflect the mechanism that promotes cellular PADI4 activation. This work contributes to our understanding of PADI4 regulation and provides a toolkit for the study and modulation of PADI4 across (patho)physiological contexts.
History
DepositionNov 30, 2023-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateNov 27, 2024-
Current statusNov 27, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19011.png

Downloads & links

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Map

FileDownload / File: emd_19011.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.95 Å/pix.
x 300 pix.
= 285. Å		0.95 Å/pix.
x 300 pix.
= 285. Å		0.95 Å/pix.
x 300 pix.
= 285. Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.95 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-2.3539789 - 3.350311
Average (Standard dev.)0.001287551 (±0.059090488)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 285.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19011_msk_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_19011_half_map_1.map
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Half map: #2

Fileemd_19011_half_map_2.map
Projections & Slices
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Sample components

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Entire : Human PADI4 in complex with cyclic peptide PADI4_3

EntireName: Human PADI4 in complex with cyclic peptide PADI4_3
Components
  • Complex: Human PADI4 in complex with cyclic peptide PADI4_3
    • Protein or peptide: Protein-arginine deiminase type-4
    • Protein or peptide: Cyclic Peptide PADI4_3
  • Ligand: CALCIUM ION

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Supramolecule #1: Human PADI4 in complex with cyclic peptide PADI4_3

SupramoleculeName: Human PADI4 in complex with cyclic peptide PADI4_3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 150 KDa

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Macromolecule #1: Protein-arginine deiminase type-4

MacromoleculeName: Protein-arginine deiminase type-4 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 74.803719 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GPLGSPQMAQ GTLIRVTPEQ PTHAVCVLGT LTQLDICSSA PDDCTSFSIN ASPGVVVDIA HSPPAKKKST GSSTWPLDPG VEVTLTMKA ASGSTGDQKV QISYYGPKTP PVKALLYLTA VEISLCADIT RTGKVKPTRA VKDQRTWTWG PCGQGAILLV N CDRDNLES ...String:
GPLGSPQMAQ GTLIRVTPEQ PTHAVCVLGT LTQLDICSSA PDDCTSFSIN ASPGVVVDIA HSPPAKKKST GSSTWPLDPG VEVTLTMKA ASGSTGDQKV QISYYGPKTP PVKALLYLTA VEISLCADIT RTGKVKPTRA VKDQRTWTWG PCGQGAILLV N CDRDNLES SAMDCEDDEV LDSEDLQDMS LMTLSTKTPK DFFTNHTLVL HVARSEMDKV RVFQATRGKL SSKCSVVLGP KW PSHYLMV PGGKHNMDFY VEALAFPDTD FPGLITLTIS LLDTSNLELP EAVVFQDSVV FRVAPWIMTP NTQPPQEVYA CSI FENEDF LKSVTTLAMK AKCKLTICPE EENMDDQWMQ DEMEIGYIQA PHKTLPVVFD SPRNRGLKEF PIKRVMGPDF GYVT RGPQT GGISGLDSFG NLEVSPPVTV RGKEYPLGRI LFGDSCYPSN DSRQMHQALQ DFLSAQQVQA PVKLYSDWLS VGHVD EFLS FVPAPDRKGF RLLLASPRSC YKLFQEQQNE GHGEALLFEG IKKKKQQKIK NILSNKTLRE HNSFVERCID WNRELL KRE LGLAESDIID IPQLFKLKEF SKAEAFFPNM VNMLVLGKHL GIPKPFGPVI NGRCCLEEKV CSLLEPLGLQ CTFINDF FT YHIRHGEVHC GTNVRRKPFS FKWWNMVP

UniProtKB: Protein-arginine deiminase type-4

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Macromolecule #2: Cyclic Peptide PADI4_3

MacromoleculeName: Cyclic Peptide PADI4_3 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 1.765995 KDa
SequenceString:
(UNK)YRDHHYRHP KYC

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 10 / Formula: CA
Molecular weightTheoretical: 40.078 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 28.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 127000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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