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- EMDB-4983: Structure of human complement C5 complexed with tick inhibitors O... -

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Basic information

Entry
Database: EMDB / ID: EMD-4983
TitleStructure of human complement C5 complexed with tick inhibitors OmCI, RaCI1 and CirpT1
Map data
Sample
  • Complex: Quaternary complex of human complement C5 with tick inhibitors OmCI, RaCI and CirpT1
    • Complex: Human Complement C5 (2)
      • Protein or peptide: Complement C5
      • Protein or peptide: Complement C5
    • Complex: Complement inhibitor
      • Protein or peptide: Complement inhibitor
    • Complex: Rhipicephalus appendiculatus RaCI1
      • Protein or peptide: Rhipicephalus appendiculatus RaCI1
    • Complex: Putative 8.9 kDa family member
      • Protein or peptide: Putative 8.9 kDa family member
Function / homology
Function and homology information


Terminal pathway of complement / membrane attack complex / Activation of C3 and C5 / negative regulation of macrophage chemotaxis / complement activation, alternative pathway / chemokine activity / endopeptidase inhibitor activity / positive regulation of vascular endothelial growth factor production / positive regulation of chemokine production / Peptide ligand-binding receptors ...Terminal pathway of complement / membrane attack complex / Activation of C3 and C5 / negative regulation of macrophage chemotaxis / complement activation, alternative pathway / chemokine activity / endopeptidase inhibitor activity / positive regulation of vascular endothelial growth factor production / positive regulation of chemokine production / Peptide ligand-binding receptors / complement activation, classical pathway / Regulation of Complement cascade / chemotaxis / toxin activity / G alpha (i) signalling events / killing of cells of another organism / cell surface receptor signaling pathway / inflammatory response / G protein-coupled receptor signaling pathway / signaling receptor binding / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
Single domain Von Willebrand factor type C domain / Single domain von Willebrand factor type C / Single domain von Willebrand factor type C / : / Complement component 5, CUB domain / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin, complement system ...Single domain Von Willebrand factor type C domain / Single domain von Willebrand factor type C / Single domain von Willebrand factor type C / : / Complement component 5, CUB domain / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin, complement system / Anaphylatoxin/fibulin / Anaphylotoxin-like domain / Anaphylatoxin domain profile. / Anaphylatoxin homologous domain / Netrin C-terminal Domain / Netrin module, non-TIMP type / UNC-6/NTR/C345C module / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor binding domain / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor / Netrin domain / NTR domain profile. / Tissue inhibitor of metalloproteinases-like, OB-fold / Alpha-2-macroglobulin / Macroglobulin domain / Alpha-2-macroglobulin, bait region domain / Alpha-macroglobulin-like, TED domain / Alpha-2-macroglobulin family / MG2 domain / A-macroglobulin TED domain / Alpha-2-macroglobulin bait region domain / Alpha-2-Macroglobulin / Alpha-2-macroglobulin family / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Calycin / Immunoglobulin-like fold
Similarity search - Domain/homology
Complement inhibitor RaCI1 / Complement inhibitor RaCI1 / Complement inhibitor CirpT1 / Complement C5 / Complement inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human) / Ornithodoros moubata (arthropod) / Rhipicephalus appendiculatus (arthropod) / Rhipicephalus pulchellus (arthropod) / Human (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsReichhardt MP / Johnson S / Lea SM
Funding support Finland, United Kingdom, 4 items
OrganizationGrant numberCountry
Finnish Cultural Foundation Finland
Wellcome Trust201536 United Kingdom
Wellcome Trust100298 United Kingdom
Wolfson FoundationWL160052 United Kingdom
CitationJournal: Proc Natl Acad Sci U S A / Year: 2020
Title: An inhibitor of complement C5 provides structural insights into activation.
Authors: Martin P Reichhardt / Steven Johnson / Terence Tang / Thomas Morgan / Nchimunya Tebeka / Niko Popitsch / Justin C Deme / Matthijs M Jore / Susan M Lea /
Abstract: The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick lasts for days, and the tick must therefore rely on inhibitors to counter ...The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick lasts for days, and the tick must therefore rely on inhibitors to counter complement activation. We have identified a class of inhibitors from tick saliva, the CirpT family, and generated detailed structural data revealing their mechanism of action. We show direct binding of a CirpT to complement C5 and have determined the structure of the C5-CirpT complex by cryoelectron microscopy. This reveals an interaction with the peripheral macro globulin domain 4 (C5_MG4) of C5. To achieve higher resolution detail, the structure of the C5_MG4-CirpT complex was solved by X-ray crystallography (at 2.7 Å). We thus present the fold of the CirpT protein family, and provide detailed mechanistic insights into its inhibitory function. Analysis of the binding interface reveals a mechanism of C5 inhibition, and provides information to expand our biological understanding of the activation of C5, and thus the terminal complement pathway.
History
DepositionMay 15, 2019-
Header (metadata) releaseMay 29, 2019-
Map releaseJan 8, 2020-
UpdateDec 2, 2020-
Current statusDec 2, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.009
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  • Surface view with fitted model
  • Atomic models: PDB-6rqj
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_4983.png

Downloads & links

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Map

FileDownload / File: emd_4983.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.822 Å
Density
Contour LevelBy AUTHOR: 0.009 / Movie #1: 0.009
Minimum - Maximum-0.014453048 - 0.03993853
Average (Standard dev.)-0.00001048280 (±0.0015173189)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 236.73601 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8220.8220.822
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z236.736236.736236.736
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-0.0140.040-0.000

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Supplemental data

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Mask #1

Fileemd_4983_msk_1.map
Projections & Slices
AxesZYX

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Additional map: #2

Fileemd_4983_additional_1.map
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Additional map: #1

Fileemd_4983_additional_2.map
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Half map: #2

Fileemd_4983_half_map_1.map
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Half map: #1

Fileemd_4983_half_map_2.map
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Sample components

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Entire : Quaternary complex of human complement C5 with tick inhibitors Om...

EntireName: Quaternary complex of human complement C5 with tick inhibitors OmCI, RaCI and CirpT1
Components
  • Complex: Quaternary complex of human complement C5 with tick inhibitors OmCI, RaCI and CirpT1
    • Complex: Human Complement C5 (2)
      • Protein or peptide: Complement C5
      • Protein or peptide: Complement C5
    • Complex: Complement inhibitor
      • Protein or peptide: Complement inhibitor
    • Complex: Rhipicephalus appendiculatus RaCI1
      • Protein or peptide: Rhipicephalus appendiculatus RaCI1
    • Complex: Putative 8.9 kDa family member
      • Protein or peptide: Putative 8.9 kDa family member

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Supramolecule #1: Quaternary complex of human complement C5 with tick inhibitors Om...

SupramoleculeName: Quaternary complex of human complement C5 with tick inhibitors OmCI, RaCI and CirpT1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightExperimental: 215 KDa

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Supramolecule #2: Human Complement C5 (2)

SupramoleculeName: Human Complement C5 (2) / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1, #4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Complement inhibitor

SupramoleculeName: Complement inhibitor / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Ornithodoros moubata (arthropod)
Recombinant expressionOrganism: Kluyveromyces lactis (yeast)

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Supramolecule #4: Rhipicephalus appendiculatus RaCI1

SupramoleculeName: Rhipicephalus appendiculatus RaCI1 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Rhipicephalus appendiculatus (arthropod)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Supramolecule #5: Putative 8.9 kDa family member

SupramoleculeName: Putative 8.9 kDa family member / type: complex / ID: 5 / Parent: 1 / Macromolecule list: #5
Source (natural)Organism: Rhipicephalus pulchellus (arthropod)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: Complement C5

MacromoleculeName: Complement C5 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human (human)
Molecular weightTheoretical: 112.635008 KDa
SequenceString: TLQKKIEEIA AKYKHSVVKK CCYDGACVNN DETCEQRAAR ISLGPRCIKA FTECCVVASQ LRANISHKDM QLGRLHMKTL LPVSKPEIR SYFPESWLWE VHLVPRRKQL QFALPDSLTT WEIQGVGISN TGICVADTVK AKVFKDVFLE MNIPYSVVRG E QIQLKGTV ...String:
TLQKKIEEIA AKYKHSVVKK CCYDGACVNN DETCEQRAAR ISLGPRCIKA FTECCVVASQ LRANISHKDM QLGRLHMKTL LPVSKPEIR SYFPESWLWE VHLVPRRKQL QFALPDSLTT WEIQGVGISN TGICVADTVK AKVFKDVFLE MNIPYSVVRG E QIQLKGTV YNYRTSGMQF CVKMSAVEGI CTSESPVIDH QGTKSSKCVR QKVEGSSSHL VTFTVLPLEI GLHNINFSLE TW FGKEILV KTLRVVPEGV KRESYSGVTL DPRGIYGTIS RRKEFPYRIP LDLVPKTEIK RILSVKGLLV GEILSAVLSQ EGI NILTHL PKGSAEAELM SVVPVFYVFH YLETGNHWNI FHSDPLIEKQ KLKKKLKEGM LSIMSYRNAD YSYSVWKGGS ASTW LTAFA LRVLGQVNKY VEQNQNSICN SLLWLVENYQ LDNGSFKENS QYQPIKLQGT LPVEARENSL YLTAFTVIGI RKAFD ICPL VKIDTALIKA DNFLLENTLP AQSTFTLAIS AYALSLGDKT HPQFRSIVSA LKREALVKGN PPIYRFWKDN LQHKDS SVP NTGTARMVET TAYALLTSLN LKDINYVNPV IKWLSEEQRY GGGFYSTQDT INAIEGLTEY SLLVKQLRLS MDIDVSY KH KGALHNYKMT DKNFLGRPVE VLLNDDLIVS TGFGSGLATV HVTTVVHKTS TSEEVCSFYL KIDTQDIEAS HYRGYGNS D YKRIVACASY KPSREESSSG SSHAVMDISL PTGISANEED LKALVEGVDQ LFTDYQIKDG HVILQLNSIP SSDFLCVRF RIFELFEVGF LSPATFTVYE YHRPDKQCTM FYSTSNIKIQ KVCEGAACKC VEADCGQMQE ELDLTISAET RKQTACKPEI AYAYKVSIT SITVENVFVK YKATLLDIYK TGEAVAEKDS EITFIKKVTC TNAELVKGRQ YLIMGKEALQ IKYNFSFRYI Y PLDSLTWI EYWPRDTTCS SCQAFLANLD EFAEDIFLNG C

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Macromolecule #2: Complement inhibitor

MacromoleculeName: Complement inhibitor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rhipicephalus pulchellus (arthropod)
Molecular weightTheoretical: 18.647588 KDa
Recombinant expressionOrganism: Kluyveromyces lactis (yeast)
SequenceString:
MASHHHHHHH HHHSGDSESD CTGSEPVDAF QAFSEGKEAY VLVRSTDPKA RDCLKGEPAG EKQDNTLPVM MTFKQGTDWA STDWTFTLD GAKVTATLGQ LTQNREVVYD SQSHHCHVDK VEKEVPDYEM WMLDAGGLEV EVECCRQKLE ELASGRNQMY P HLKDC

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Macromolecule #3: Rhipicephalus appendiculatus RaCI1

MacromoleculeName: Rhipicephalus appendiculatus RaCI1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rhipicephalus pulchellus (arthropod)
Molecular weightTheoretical: 8.57675 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GPMEEVKTTP IPNHQCVNAT CERKLDALGN AVITKCPQGC LCVVRGASNI VPANGTCFQL ATTKPPMAPG DNKDNKEEES N

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Macromolecule #4: Complement C5

MacromoleculeName: Complement C5 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human (human)
Molecular weightTheoretical: 73.361453 KDa
SequenceString: QEQTYVISAP KIFRVGASEN IVIQVYGYTE AFDATISIKS YPDKKFSYSS GHVHLSSENK FQNSAILTIQ PKQLPGGQNP VSYVYLEVV SKHFSKSKRM PITYDNGFLF IHTDKPVYTP DQSVKVRVYS LNDDLKPAKR ETVLTFIDPE GSEVDMVEEI D HIGIISFP ...String:
QEQTYVISAP KIFRVGASEN IVIQVYGYTE AFDATISIKS YPDKKFSYSS GHVHLSSENK FQNSAILTIQ PKQLPGGQNP VSYVYLEVV SKHFSKSKRM PITYDNGFLF IHTDKPVYTP DQSVKVRVYS LNDDLKPAKR ETVLTFIDPE GSEVDMVEEI D HIGIISFP DFKIPSNPRY GMWTIKAKYK EDFSTTGTAY FEVKEYVLPH FSVSIEPEYN FIGYKNFKNF EITIKARYFY NK VVTEADV YITFGIREDL KDDQKEMMQT AMQNTMLING IAQVTFDSET AVKELSYYSL EDLNNKYLYI AVTVIESTGG FSE EAEIPG IKYVLSPYKL NLVATPLFLK PGIPYPIKVQ VKDSLDQLVG GVPVTLNAQT IDVNQETSDL DPSKSVTRVD DGVA SFVLN LPSGVTVLEF NVKTDAPDLP EENQAREGYR AIAYSSLSQS YLYIDWTDNH KALLVGEHLN IIVTPKSPYI DKITH YNYL ILSKGKIIHF GTREKFSDAS YQSINIPVTQ NMVPSSRLLV YYIVTGEQTA ELVSDSVWLN IEEKCGNQLQ VHLSPD ADA YSPGQTVSLN MATGMDSWVA LAAVDSAVYG VQRGAKKPLE RVFQFLEKSD LGCGAGGGLN NANVFHLAGL TFLTNAN AD DSQENDEPCK EIL

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Macromolecule #5: Putative 8.9 kDa family member

MacromoleculeName: Putative 8.9 kDa family member / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rhipicephalus pulchellus (arthropod)
Molecular weightTheoretical: 12.153626 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
KHHHHHHSAG LEVLFQGPMG DVQERGHTYV TKNVTVEDGA CVYLRNVIPN GETKALNNPC VLSTCYAADR KVNSTLCPNI GVDEGCHVE WTPDGVYPNC CPKHVCPSAT ASS

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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

Concentration0.3 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
137.0 mMNaClsodium chloride
2.7 mMKClpotassium chloride
10.0 mMPO4phosphate
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 4440 / Average exposure time: 8.0 sec. / Average electron dose: 48.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 502640
CTF correctionSoftware - Name: CTFFIND (ver. 4.1.8)
Startup modelType of model: INSILICO MODEL / In silico model: Generated using Relion 3.0 Initial Model
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 118634
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 2.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

5hce


6rpt

chain_id: B
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6rqj:
Structure of human complement C5 complexed with tick inhibitors OmCI, RaCI1 and CirpT1

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