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- EMDB-15713: Structure of Complement C5 in Complex with small molecule inhibit... -

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Basic information

Entry
Database: EMDB / ID: EMD-15713
TitleStructure of Complement C5 in Complex with small molecule inhibitor and CVF
Map data
Sample
  • Complex: Complement C5-Inhibitor-CVF complex
    • Protein or peptide: Cobra venom factor
  • Protein or peptide: Complement C5 beta chain
  • Protein or peptide: Complement C5 alpha chain
  • Ligand: 5-methoxy-2-[[(1~{S})-1-(2-methoxyphenyl)ethyl]carbamoylamino]-4-(4-methylpentoxy)benzoic acid
  • Ligand: MAGNESIUM ION
KeywordsInhibitor / Protease / Complex / Cryo-EM / Toxin / IMMUNE SYSTEM
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 / complement activation, alternative pathway / chemokine activity / endopeptidase inhibitor activity / positive regulation of vascular endothelial growth factor production / complement activation, classical pathway ...Terminal pathway of complement / membrane attack complex / Activation of C3 and C5 / negative regulation of macrophage chemotaxis / complement activation / complement activation, alternative pathway / chemokine activity / endopeptidase inhibitor activity / positive regulation of vascular endothelial growth factor production / complement activation, classical pathway / positive regulation of chemokine production / Peptide ligand-binding receptors / Regulation of Complement cascade / chemotaxis / toxin activity / G alpha (i) signalling events / killing of cells of another organism / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / inflammatory response / signaling receptor binding / extracellular space / extracellular exosome / extracellular region / metal ion binding
Similarity search - Function
: / Complement component 5, CUB domain / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 ...: / Complement component 5, CUB domain / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / : / Anaphylatoxin domain signature. / Alpha-macro-globulin thiol-ester bond-forming region / 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 / Macroglobulin domain MG4 / Macroglobulin domain MG4 / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Netrin domain / NTR domain profile. / Alpha-2-macroglobulin / Macroglobulin domain / Tissue inhibitor of metalloproteinases-like, OB-fold / 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 / Immunoglobulin-like fold
Similarity search - Domain/homology
Complement C5 / Cobra venom factor
Similarity search - Component
Biological speciesHomo sapiens (human) / Naja kaouthia (monocled cobra)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsSrinivas H
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Other private Switzerland
CitationJournal: Nat Chem Biol / Year: 2019
Title: A small-molecule inhibitor of C5 complement protein.
Authors: Keith Jendza / Mitsunori Kato / Michael Salcius / Honnappa Srinivas / Andrea De Erkenez / Anh Nguyen / Doug McLaughlin / Celine Be / Christian Wiesmann / Jason Murphy / Philippe Bolduc / ...Authors: Keith Jendza / Mitsunori Kato / Michael Salcius / Honnappa Srinivas / Andrea De Erkenez / Anh Nguyen / Doug McLaughlin / Celine Be / Christian Wiesmann / Jason Murphy / Philippe Bolduc / Muneto Mogi / Jose Duca / Abdel Namil / Michael Capparelli / Veronique Darsigny / Erik Meredith / Ritesh Tichkule / Luciana Ferrara / Jessica Heyder / Fang Liu / Patricia A Horton / Michael J Romanowski / Markus Schirle / Nello Mainolfi / Karen Anderson / Gregory A Michaud /
Abstract: The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target ...The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein.
History
DepositionSep 2, 2022-
Header (metadata) releaseDec 21, 2022-
Map releaseDec 21, 2022-
SupersessionApr 19, 2023ID: EMD-4401
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15713.png

Downloads & links

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Map

FileDownload / File: emd_15713.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 300 pix.
= 258. Å		0.86 Å/pix.
x 300 pix.
= 258. Å		0.86 Å/pix.
x 300 pix.
= 258. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.118337534 - 0.23124841
Average (Standard dev.)0.00063536013 (±0.006734457)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 258.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_15713_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_15713_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complement C5-Inhibitor-CVF complex

EntireName: Complement C5-Inhibitor-CVF complex
Components
  • Complex: Complement C5-Inhibitor-CVF complex
    • Protein or peptide: Cobra venom factor
  • Protein or peptide: Complement C5 beta chain
  • Protein or peptide: Complement C5 alpha chain
  • Ligand: 5-methoxy-2-[[(1~{S})-1-(2-methoxyphenyl)ethyl]carbamoylamino]-4-(4-methylpentoxy)benzoic acid
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Complement C5-Inhibitor-CVF complex

SupramoleculeName: Complement C5-Inhibitor-CVF complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 320 KDa

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Macromolecule #1: Complement C5 beta chain

MacromoleculeName: Complement C5 beta chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 73.615766 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 EILRP

UniProtKB: Complement C5

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Macromolecule #2: Complement C5 alpha chain

MacromoleculeName: Complement C5 alpha chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (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

UniProtKB: Complement C5

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Macromolecule #3: Cobra venom factor

MacromoleculeName: Cobra venom factor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Naja kaouthia (monocled cobra)
Molecular weightTheoretical: 184.726734 KDa
SequenceString: MERMALYLVA ALLIGFPGSS HGALYTLITP AVLRTDTEEQ ILVEAHGDST PKQLDIFVHD FPRKQKTLFQ TRVDMNPAGG MLVTPTIEI PAKEVSTDSR QNQYVVVQVT GPQVRLEKVV LLSYQSSFLF IQTDKGIYTP GSPVLYRVFS MDHNTSKMNK T VIVEFQTP ...String:
MERMALYLVA ALLIGFPGSS HGALYTLITP AVLRTDTEEQ ILVEAHGDST PKQLDIFVHD FPRKQKTLFQ TRVDMNPAGG MLVTPTIEI PAKEVSTDSR QNQYVVVQVT GPQVRLEKVV LLSYQSSFLF IQTDKGIYTP GSPVLYRVFS MDHNTSKMNK T VIVEFQTP EGILVSSNSV DLNFFWPYNL PDLVSLGTWR IVAKYEHSPE NYTAYFDVRK YVLPSFEVRL QPSEKFFYID GN ENFHVSI TARYLYGEEV EGVAFVLFGV KIDDAKKSIP DSLTRIPIID GDGKATLKRD TFRSRFPNLN ELVGHTLYAS VTV MTESGS DMVVTEQSGI HIVASPYQIH FTKTPKYFKP GMPYELTVYV TNPDGSPAAH VPVVSEAFHS MGTTLSDGTA KLIL NIPLN AQSLPITVRT NHGDLPRERQ ATKSMTAIAY QTQGGSGNYL HVAITSTEIK PGDNLPVNFN VKGNANSLKQ IKYFT YLIL NKGKIFKVGR QPRRDGQNLV TMNLHITPDL IPSFRFVAYY QVGNNEIVAD SVWVDVKDTC MGTLVVKGDN LIQMPG AAM KIKLEGDPGA RVGLVAVDKA VYVLNDKYKI SQAKIWDTIE KSDFGCTAGS GQNNLGVFED AGLALTTSTN LNTKQRS AA KCPQPANRRR RSSVLLLDSN ASKAAEFQDQ DLRKCCEDVM HENPMGYTCE KRAKYIQEGD ACKAAFLECC RYIKGVRD E NQRESELFLA RDDNEDGFIA DSDIISRSDF PKSWLWLTKD LTEEPNSQGI SSKTMSFYLR DSITTWVVLA VSFTPTKGI CVAEPYEIRV MKVFFIDLQM PYSVVKNEQV EIRAILHNYV NEDIYVRVEL LYNPAFCSAS TKGQRYRQQF PIKALSSRAV PFVIVPLEQ GLHDVEIKAS VQEALWSDGV RKKLKVVPEG VQKSIVTIVK LDPRAKGVGG TQLEVIKARK LDDRVPDTEI E TKIIIQGD PVAQIIENSI DGSKLNHLII TPSGCGEQNM IRMAAPVIAT YYLDTTEQWE TLGINRRTEA VNQIVTGYAQ QM VYKKADH SYAAFTNRAS SSWLTAYVVK VFAMAAKMVA GISHEIICGG VRWLILNRQQ PDGAFKENAP VLSGTMQGGI QGA EEEVYL TAFILVALLE SKTICNDYVN SLDSSIKKAT NYLLKKYEKL QRPYTTALTA YALAAADQLN DDRVLMAAST GRDH WEEYN AHTHNIEGTS YALLALLKMK KFDQTGPIVR WLTDQNFYGE TYGQTQATVM AFQALAEYEI QMPTHKDLNL DITIE LPDR EVPIRYRINY ENALLARTVE TKLNQDITVT ASGDGKATMT ILTFYNAQLQ EKANVCNKFH LNVSVENIHL NAMGAK GAL MLKICTRYLG EVDSTMTIID ISMLTGFLPD AEDLTRLSKG VDRYISRYEV DNNMAQKVAV IIYLNKVSHS EDECLHF KI LKHFEVGFIQ PGSVKVYSYY NLDEKCTKFY HPDKGTGLLN KICIGNVCRC AGETCSSLNH QERIDVPLQI EKACETNV D YVYKTKLLRI EEQDGNDIYV MDVLEVIKQG TDENPRAKTH QYISQRKCQE ALNLKVNDDY LIWGSRSDLL PTKDKISYI ITKNTWIERW PHEDECQEEE FQKLCDDFAQ FSYTLTEFGC PT

UniProtKB: Cobra venom factor

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Macromolecule #4: 5-methoxy-2-[[(1~{S})-1-(2-methoxyphenyl)ethyl]carbamoylamino]-4-...

MacromoleculeName: 5-methoxy-2-[[(1~{S})-1-(2-methoxyphenyl)ethyl]carbamoylamino]-4-(4-methylpentoxy)benzoic acid
type: ligand / ID: 4 / Number of copies: 1 / Formula: H1H
Molecular weightTheoretical: 444.521 Da
Chemical component information

ChemComp-H1H:
5-methoxy-2-[[(1~{S})-1-(2-methoxyphenyl)ethyl]carbamoylamino]-4-(4-methylpentoxy)benzoic acid

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Macromolecule #5: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 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 / Details: 50mM HEPES pH 7.5 100mM NaCl
VitrificationCryogen name: ETHANE
DetailsComplement C5-Inhibitor-CVF complex

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 1.4 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

3pvm

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 351000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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