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- PDB-8ayh: Structure of Complement C5 in Complex with small molecule inhibit... -

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Basic information

Entry
Database: PDB / ID: 8ayh
TitleStructure of Complement C5 in Complex with small molecule inhibitor and CVF
Components
  • Cobra venom factor
  • Complement C5 alpha chain
  • Complement C5 beta chain
KeywordsIMMUNE SYSTEM / Inhibitor / Protease / Complex / Cryo-EM / Toxin
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 / complement activation / chemokine activity / endopeptidase inhibitor activity / positive regulation of vascular endothelial growth factor production / positive regulation of chemokine production ...Terminal pathway of complement / membrane attack complex / Activation of C3 and C5 / negative regulation of macrophage chemotaxis / complement activation, alternative pathway / complement activation / 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 / metal ion binding
Similarity search - Function
: / Complement component 5, CUB domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Complement C3-like, NTR domain / 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 component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Complement C3-like, NTR domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / : / Alpha-macro-globulin thiol-ester bond-forming region / 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 / Immunoglobulin-like fold
Similarity search - Domain/homology
Chem-H1H / Complement C5 / Cobra venom factor
Similarity search - Component
Biological speciesHomo sapiens (human)
Naja kaouthia (monocled cobra)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsSrinivas, H.
Funding support Switzerland, 1items
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, 2022Deposition site: PDBE / Processing site: PDBE
SupersessionDec 21, 2022ID: 6I2X
Revision 1.0Dec 21, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: Complement C5 beta chain
A: Complement C5 alpha chain
B: Cobra venom factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)371,4465
Polymers370,9783
Non-polymers4692
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13720 Å2
ΔGint-75 kcal/mol
Surface area102960 Å2
MethodPISA

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Components

#1: Protein Complement C5 beta chain


Mass: 73615.766 Da / Num. of mol.: 1 / Fragment: beta chain, UNP residues 1-675 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P01031
#2: Protein Complement C5 alpha chain


Mass: 112635.008 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P01031
#3: Protein Cobra venom factor / CVFk / Complement C3 homolog


Mass: 184726.734 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Naja kaouthia (monocled cobra) / References: UniProt: Q91132
#4: Chemical ChemComp-H1H / 5-methoxy-2-[[(1~{S})-1-(2-methoxyphenyl)ethyl]carbamoylamino]-4-(4-methylpentoxy)benzoic acid


Mass: 444.521 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32N2O6 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complement C5-Inhibitor-CVF complex / Type: COMPLEX / Entity ID: #3 / Source: NATURAL
Molecular weightValue: 0.320 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5 / Details: 50mM HEPES pH 7.5 100mM NaCl
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Complement C5-Inhibitor-CVF complex
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 1.4 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 351000 / Symmetry type: POINT

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