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- EMDB-8092: Structure of the quaternary complex of complement C5 with two tic... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-8092 | |||||||||
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Title | Structure of the quaternary complex of complement C5 with two tick inhibitors (OmCI and RaCI) and a Fab derived from the therapeutic Eculizumab | |||||||||
![]() | None | |||||||||
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Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / negative staining / Resolution: 16.0 Å | |||||||||
![]() | Lea SM / Elmlund H | |||||||||
![]() | ![]() 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 |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 141 KB | ![]() | |
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Header (meta data) | ![]() ![]() | 13 KB 13 KB | Display Display | ![]() |
Images | ![]() | 18.4 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
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Links
EMDB pages | ![]() ![]() |
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Map
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Annotation | None | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 4.12 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : Complex of Complement C5 with two tick inihibitors and Fab fragme...
Entire | Name: Complex of Complement C5 with two tick inihibitors and Fab fragment derived from Eculizumab |
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Components |
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-Supramolecule #1: Complex of Complement C5 with two tick inihibitors and Fab fragme...
Supramolecule | Name: Complex of Complement C5 with two tick inihibitors and Fab fragment derived from Eculizumab type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Molecular weight | Experimental: 266 KDa |
-Macromolecule #1: complement C5
Macromolecule | Name: complement C5 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #2: OmCI
Macromolecule | Name: OmCI / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Sequence | String: MLVLVTLIFS FSANIAYADS ESDCTGSEPV DAFQAFSEGK EAYVLVRSTD PKARDCLKGE PAGEKQDNT LPVMMTFKNG TDWASTDWTF TLDGAKVTAT LGNLTQNREV VYDSQSHHCH V DKVEKEVP DYEMWMLDAG GLEVEVECCR QKLEELASGR NQMYPHLKDC |
-Macromolecule #3: RaCI
Macromolecule | Name: RaCI / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Sequence | String: EEVKTTPIPN HQCVNATCER KLDALGNAVI TKCPQGCLCV VRGASNIVPA NGTCFQLATT KPPMAPGDNK DNKEEESN |
-Macromolecule #4: Recombinant Fab with Eculizumab variable regions
Macromolecule | Name: Recombinant Fab with Eculizumab variable regions / type: protein_or_peptide / ID: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Synthetic construct (others) |
Sequence | String: 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 |
-Experimental details
-Structure determination
Method | negative staining |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Staining | Type: NEGATIVE / Material: Uranyl Acetate |
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Electron microscopy
Microscope | FEI TECNAI SPIRIT |
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Image recording | Film or detector model: FEI EAGLE (4k x 4k) / Average electron dose: 25.0 e/Å2 |
Electron beam | Acceleration voltage: 120 kV / Electron source: LAB6 |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Tecnai Spirit / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Resolution.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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Initial angle assignment | Type: NOT APPLICABLE / Software - Name: PRIME (ver. 2.0) Details: Probabilistic projection matching using the PRIME algorithm |
Final angle assignment | Type: OTHER / Software - Name: PRIME (ver. 2.0) Details: Probabilistic projection matching using the PRIME algorithm |