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- EMDB-8092: Structure of the quaternary complex of complement C5 with two tic... -

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Basic information

Entry
Database: EMDB / ID: EMD-8092
TitleStructure of the quaternary complex of complement C5 with two tick inhibitors (OmCI and RaCI) and a Fab derived from the therapeutic Eculizumab
Map dataNone
Sample
  • Complex: Complex of Complement C5 with two tick inihibitors and Fab fragment derived from Eculizumab
    • Protein or peptide: complement C5Complement component 5
    • Protein or peptide: OmCI
    • Protein or peptide: RaCI
    • Protein or peptide: Recombinant Fab with Eculizumab variable regions
Biological speciesHuman (human) / Rhipicephalus appendiculatus (arthropod) / Synthetic construct (others)
Methodsingle particle reconstruction / negative staining / Resolution: 16.0 Å
AuthorsLea SM / Elmlund H
CitationJournal: Nat Struct Mol Biol / Year: 2016
Title: Structural basis for therapeutic inhibition of complement C5.
Authors: Matthijs M Jore / Steven Johnson / Devon Sheppard / Natalie M Barber / Yang I Li / Miles A Nunn / Hans Elmlund / Susan M Lea /
Abstract: Activation of complement C5 generates the potent anaphylatoxin C5a and leads to pathogen lysis, inflammation and cell damage. The therapeutic potential of C5 inhibition has been demonstrated by ...Activation of complement C5 generates the potent anaphylatoxin C5a and leads to pathogen lysis, inflammation and cell damage. The therapeutic potential of C5 inhibition has been demonstrated by eculizumab, one of the world's most expensive drugs. However, the mechanism of C5 activation by C5 convertases remains elusive, thus limiting development of therapeutics. Here we identify and characterize a new protein family of tick-derived C5 inhibitors. Structures of C5 in complex with the new inhibitors, the phase I and phase II inhibitor OmCI, or an eculizumab Fab reveal three distinct binding sites on C5 that all prevent activation of C5. The positions of the inhibitor-binding sites and the ability of all three C5-inhibitor complexes to competitively inhibit the C5 convertase conflict with earlier steric-inhibition models, thus suggesting that a priming event is needed for activation.
History
DepositionFeb 28, 2016-
Header (metadata) releaseApr 13, 2016-
Map releaseApr 13, 2016-
UpdateJun 15, 2016-
Current statusJun 15, 2016Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.86
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 1.86
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8092.png

Downloads & links

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Map

FileDownload / File: emd_8092.map.gz / Format: CCP4 / Size: 2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNone
Voxel sizeX=Y=Z: 4.12 Å
Density
Contour LevelBy AUTHOR: 1.86 / Movie #1: 1.86
Minimum - Maximum-4.155845 - 22.340123999999999
Average (Standard dev.)0.11045824 (±0.9147426)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-40-40-40
Dimensions808080
Spacing808080
CellA=B=C: 329.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z4.124.124.12
M x/y/z808080
origin x/y/z0.0000.0000.000
length x/y/z329.600329.600329.600
α/β/γ90.00090.00090.000
start NX/NY/NZ-25-77-48
NX/NY/NZ899896
MAP C/R/S123
start NC/NR/NS-40-40-40
NC/NR/NS808080
D min/max/mean-4.15622.3400.110

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Supplemental data

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Sample components

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Entire : Complex of Complement C5 with two tick inihibitors and Fab fragme...

EntireName: Complex of Complement C5 with two tick inihibitors and Fab fragment derived from Eculizumab
Components
  • Complex: Complex of Complement C5 with two tick inihibitors and Fab fragment derived from Eculizumab
    • Protein or peptide: complement C5Complement component 5
    • Protein or peptide: OmCI
    • Protein or peptide: RaCI
    • Protein or peptide: Recombinant Fab with Eculizumab variable regions

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Supramolecule #1: Complex of Complement C5 with two tick inihibitors and Fab fragme...

SupramoleculeName: Complex of Complement C5 with two tick inihibitors and Fab fragment derived from Eculizumab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightExperimental: 266 KDa

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Macromolecule #1: complement C5

MacromoleculeName: complement C5 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Human (human) / Tissue: Serum
SequenceString: MGLLGILCFL IFLGKTWGQE QTYVISAPKI FRVGASENIV IQVYGYTEAF DATISIKSYP DKKFSYSSG HVHLSSENKF QNSAILTIQP KQLPGGQNPV SYVYLEVVSK HFSKSKRMPI T YDNGFLFI HTDKPVYTPD QSVKVRVYSL NDDLKPAKRE TVLTFIDPEG ...String:
MGLLGILCFL IFLGKTWGQE QTYVISAPKI FRVGASENIV IQVYGYTEAF DATISIKSYP DKKFSYSSG HVHLSSENKF QNSAILTIQP KQLPGGQNPV SYVYLEVVSK HFSKSKRMPI T YDNGFLFI HTDKPVYTPD QSVKVRVYSL NDDLKPAKRE TVLTFIDPEG SEVDMVEEID HI GIISFPD FKIPSNPRYG MWTIKAKYKE DFSTTGTAYF EVKEYVLPHF SVSIEPEYNF IGY KNFKNF EITIKARYFY NKVVTEADVY ITFGIREDLK DDQKEMMQTA MQNTMLINGI AQVT FDSET AVKELSYYSL EDLNNKYLYI AVTVIESTGG FSEEAEIPGI KYVLSPYKLN LVATP LFLK PGIPYPIKVQ VKDSLDQLVG GVPVTLNAQT IDVNQETSDL DPSKSVTRVD DGVASF VLN LPSGVTVLEF NVKTDAPDLP EENQAREGYR AIAYSSLSQS YLYIDWTDNH KALLVGE HL NIIVTPKSPY IDKITHYNYL ILSKGKIIHF GTREKFSDAS YQSINIPVTQ NMVPSSRL L VYYIVTGEQT AELVSDSVWL NIEEKCGNQL QVHLSPDADA YSPGQTVSLN MATGMDSWV ALAAVDSAVY GVQRGAKKPL ERVFQFLEKS DLGCGAGGGL NNANVFHLAG LTFLTNANAD DSQENDEPC KEILRPRRTL QKKIEEIAAK YKHSVVKKCC YDGACVNNDE TCEQRAARIS L GPRCIKAF TECCVVASQL RANISHKDMQ LGRLHMKTLL PVSKPEIRSY FPESWLWEVH LV PRRKQLQ FALPDSLTTW EIQGVGISNT GICVADTVKA KVFKDVFLEM NIPYSVVRGE QIQ LKGTVY NYRTSGMQFC VKMSAVEGIC TSESPVIDHQ GTKSSKCVRQ KVEGSSSHLV TFTV LPLEI GLHNINFSLE TWFGKEILVK TLRVVPEGVK RESYSGVTLD PRGIYGTISR RKEFP YRIP LDLVPKTEIK RILSVKGLLV GEILSAVLSQ EGINILTHLP KGSAEAELMS VVPVFY VFH YLETGNHWNI FHSDPLIEKQ KLKKKLKEGM LSIMSYRNAD YSYSVWKGGS ASTWLTA FA LRVLGQVNKY VEQNQNSICN SLLWLVENYQ LDNGSFKENS QYQPIKLQGT LPVEAREN S LYLTAFTVIG IRKAFDICPL VKIDTALIKA DNFLLENTLP AQSTFTLAIS AYALSLGDK THPQFRSIVS ALKREALVKG NPPIYRFWKD NLQHKDSSVP NTGTARMVET TAYALLTSLN LKDINYVNP VIKWLSEEQR YGGGFYSTQD TINAIEGLTE YSLLVKQLRL SMDIDVSYKH K GALHNYKM TDKNFLGRPV EVLLNDDLIV STGFGSGLAT VHVTTVVHKT STSEEVCSFY LK IDTQDIE ASHYRGYGNS DYKRIVACAS YKPSREESSS GSSHAVMDIS LPTGISANEE DLK ALVEGV DQLFTDYQIK DGHVILQLNS IPSSDFLCVR FRIFELFEVG FLSPATFTVY EYHR PDKQC TMFYSTSNIK IQKVCEGAAC KCVEADCGQM QEELDLTISA ETRKQTACKP EIAYA YKVS ITSITVENVF VKYKATLLDI YKTGEAVAEK DSEITFIKKV TCTNAELVKG RQYLIM GKE ALQIKYNFSF RYIYPLDSLT WIEYWPRDTT CSSCQAFLAN LDEFAEDIFL NGC

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Macromolecule #2: OmCI

MacromoleculeName: OmCI / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Rhipicephalus appendiculatus (arthropod)
SequenceString:
MLVLVTLIFS FSANIAYADS ESDCTGSEPV DAFQAFSEGK EAYVLVRSTD PKARDCLKGE PAGEKQDNT LPVMMTFKNG TDWASTDWTF TLDGAKVTAT LGNLTQNREV VYDSQSHHCH V DKVEKEVP DYEMWMLDAG GLEVEVECCR QKLEELASGR NQMYPHLKDC

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Macromolecule #3: RaCI

MacromoleculeName: RaCI / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Rhipicephalus appendiculatus (arthropod)
SequenceString:
EEVKTTPIPN HQCVNATCER KLDALGNAVI TKCPQGCLCV VRGASNIVPA NGTCFQLATT KPPMAPGDNK DNKEEESN

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Macromolecule #4: Recombinant Fab with Eculizumab variable regions

MacromoleculeName: Recombinant Fab with Eculizumab variable regions / type: protein_or_peptide / ID: 4 / Enantiomer: LEVO
Source (natural)Organism: Synthetic construct (others)
SequenceString: QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY ME LSSLRSE DTAVYYCARY FFGSSPNWYF DVWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNS GAL ...String:
QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY ME LSSLRSE DTAVYYCARY FFGSSPNWYF DVWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNS GAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVHHHHHHHH HH DIQMTQS PSSLSASVGD RVTITCGASE NIYGALNWYQ RKPGKAPKLL IYGATNLADG VPSRFSGSGS GTDFTLTISS LQPEDFAT Y YCQNVLNTPL TFGQGTKLEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSK DSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

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Experimental details

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Structure determination

Methodnegative staining
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
StainingType: NEGATIVE / Material: Uranyl Acetate

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Electron microscopy

MicroscopeFEI TECNAI SPIRIT
Electron beamAcceleration voltage: 120 kV / Electron source: LAB6
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: FEI EAGLE (4k x 4k) / Average electron dose: 25.0 e/Å2
Experimental equipment
Model: Tecnai Spirit / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE / Software - Name: PRIME (ver. 2.0)
Details: Probabilistic projection matching using the PRIME algorithm
Final angle assignmentType: OTHER / Software - Name: PRIME (ver. 2.0)
Details: Probabilistic projection matching using the PRIME algorithm
Final reconstructionResolution.type: BY AUTHOR / Resolution: 16.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: PRIME
Details: Low-pass limited refinement at 20 ? gave 16 ? using the FSC=0.143 criterion. Perhaps you should give low-pass limited refinement as an option given that it works as well as gold-standard ...Details: Low-pass limited refinement at 20 ? gave 16 ? using the FSC=0.143 criterion. Perhaps you should give low-pass limited refinement as an option given that it works as well as gold-standard refinement for eliminating overfitting?
Number images used: 5587

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