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- PDB-5hcd: Ternary complex of human Complement C5 with Ornithodoros moubata ... -

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Basic information

Entry
Database: PDB / ID: 5hcd
TitleTernary complex of human Complement C5 with Ornithodoros moubata OmCI and Rhipicephalus microplus RaCI2
Components
  • (Complement C5Complement component 5) x 2
  • Complement inhibitor
  • Rhipicephalus microplus RaCI2
KeywordsIMMUNE SYSTEM / Complement / Inflammation / Inhibitor / Tick
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 / complement activation, classical pathway / 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 / 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 / G alpha (i) signalling events / toxin activity / 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
: / Complement component 5, CUB domain / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin/fibulin / Anaphylatoxin, complement system / Anaphylotoxin-like domain / Anaphylatoxin domain profile. ...: / Complement component 5, CUB domain / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin/fibulin / Anaphylatoxin, complement system / Anaphylotoxin-like domain / Anaphylatoxin domain profile. / Anaphylatoxin homologous domain / Netrin C-terminal Domain / Netrin module, non-TIMP type / UNC-6/NTR/C345C module / Netrin domain / NTR domain profile. / 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 / 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 beta-barrel core domain / Calycin / Lipocalin / Immunoglobulin-like fold / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
CYSTEINE / Rhipicephalus microplus RaCI2 / Complement C5 / Complement inhibitor
Similarity search - Component
Biological speciesOrnithodoros moubata (arthropod)
Rhipicephalus microplus (southern cattle tick)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.98 Å
AuthorsJore, M.M. / Johnson, S. / Lea, S.M.
Funding support United Kingdom, Netherlands, 2items
OrganizationGrant numberCountry
Wellcome Trust100298 United Kingdom
Netherlands Organisation for Scientific Research825.11.030 Netherlands
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
DepositionJan 4, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Mar 30, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 6, 2016Group: Database references
Revision 1.2May 11, 2016Group: Database references
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_unobs_or_zero_occ_atoms / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Complement C5
A: Complement C5
C: Complement inhibitor
D: Rhipicephalus microplus RaCI2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)213,9056
Polymers213,3604
Non-polymers5462
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13000 Å2
ΔGint-51 kcal/mol
Surface area83280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.954, 140.207, 209.792
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 4 types, 4 molecules BACD

#1: Protein Complement C5 / Complement component 5 / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 4


Mass: 73518.648 Da / Num. of mol.: 1 / Fragment: UNP Residues 19-674 / Source method: isolated from a natural source
Details: Chains A and B are the product of a single gene that is processed into two chains that remain covalently linked via a disulphide.
Source: (natural) Homo sapiens (human) / References: UniProt: P01031
#2: Protein Complement C5 / Complement component 5 / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 4


Mass: 112533.906 Da / Num. of mol.: 1 / Fragment: UNP Residues 679-1676 / Source method: isolated from a natural source
Details: Chains A and B are the product of a single gene that is processed into two chains that remain covalently linked via a disulphide.
Source: (natural) Homo sapiens (human) / References: UniProt: P01031
#3: Protein Complement inhibitor


Mass: 18647.588 Da / Num. of mol.: 1 / Fragment: UNP residues 19-168 / Mutation: N78Q, N102Q
Source method: isolated from a genetically manipulated source
Details: N-terminal residues are His-tag from vector / Source: (gene. exp.) Ornithodoros moubata (arthropod) / Gene: CI / Plasmid: pKLAC2 / Production host: Kluyveromyces lactis (yeast) / References: UniProt: Q5YD59
#4: Protein Rhipicephalus microplus RaCI2


Mass: 8659.689 Da / Num. of mol.: 1 / Fragment: UNP residues 28-81
Source method: isolated from a genetically manipulated source
Details: First 3 residues are remnants of expression tag. Native mature sequence starts EEAN.
Source: (gene. exp.) Rhipicephalus microplus (southern cattle tick)
Plasmid: pET-M14 / Production host: Escherichia coli K-12 (bacteria) / Variant (production host): Shuffle T7 / References: UniProt: A0A158RFT4*PLUS

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Sugars / Non-polymers , 2 types, 2 molecules

#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Chemical ChemComp-CYS / CYSTEINE / Cysteine


Type: L-peptide linking / Mass: 121.158 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H7NO2S

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.7 Å3/Da / Density % sol: 66 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 10% (w/v) PEG 20K, 2%(v/v)1,4 Dioxane, 0.1M Bicine pH 9.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.98→116.57 Å / Num. obs: 64434 / % possible obs: 97 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.11 / Rsym value: 0.138 / Net I/σ(I): 8.1
Reflection shellResolution: 2.98→3.16 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.89 / Mean I/σ(I) obs: 1.6 / % possible all: 96

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3CU7, 2CM4

3cu7

2cm4


Resolution: 2.98→74.544 Å / SU ML: 0.46 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 29.94 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.282 3185 4.97 %Random
Rwork0.2574 ---
obs0.2586 64037 99.19 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.98→74.544 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14412 0 34 0 14446
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01114770
X-RAY DIFFRACTIONf_angle_d0.88820045
X-RAY DIFFRACTIONf_dihedral_angle_d12.1158952
X-RAY DIFFRACTIONf_chiral_restr0.0572277
X-RAY DIFFRACTIONf_plane_restr0.0062552
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.98-3.02450.41891410.40522587X-RAY DIFFRACTION98
3.0245-3.07180.41991510.39642593X-RAY DIFFRACTION99
3.0718-3.12210.4091340.39872613X-RAY DIFFRACTION99
3.1221-3.1760.34071190.37432629X-RAY DIFFRACTION99
3.176-3.23370.37261460.36962541X-RAY DIFFRACTION98
3.2337-3.29590.3351300.35122646X-RAY DIFFRACTION99
3.2959-3.36320.34781590.3632597X-RAY DIFFRACTION100
3.3632-3.43630.35781570.34672593X-RAY DIFFRACTION98
3.4363-3.51620.34081350.32662612X-RAY DIFFRACTION99
3.5162-3.60420.28751450.3092630X-RAY DIFFRACTION100
3.6042-3.70160.3241420.30132609X-RAY DIFFRACTION99
3.7016-3.81050.3911290.28212655X-RAY DIFFRACTION100
3.8105-3.93350.31451260.28472604X-RAY DIFFRACTION98
3.9335-4.07410.2731540.26712618X-RAY DIFFRACTION99
4.0741-4.23720.26811470.25592633X-RAY DIFFRACTION100
4.2372-4.430.25471380.21912656X-RAY DIFFRACTION100
4.43-4.66360.21091130.20582690X-RAY DIFFRACTION100
4.6636-4.95570.20731200.19952683X-RAY DIFFRACTION100
4.9557-5.33820.23221430.19572681X-RAY DIFFRACTION99
5.3382-5.87520.25791440.2132686X-RAY DIFFRACTION100
5.8752-6.72490.29081350.22962707X-RAY DIFFRACTION100
6.7249-8.47080.2361280.2042739X-RAY DIFFRACTION99
8.4708-74.56720.19981490.18772850X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.7751-0.31380.81381.1859-0.83612.72640.03910.2618-0.1755-0.27480.076-0.00030.22020.2828-0.10250.506-0.0122-0.02760.6750.00970.5936-5.6759-27.0623-5.468
21.81820.5787-1.31921.2903-1.20962.0838-0.04640.28-0.661-0.2288-0.20660.13870.2516-0.22780.22440.61760.0584-0.17170.7991-0.14340.8368-11.4025-44.009624.3582
31.1124-0.7881-0.24841.36720.20251.14330.0114-0.03060.05060.09120.02040.0706-0.1358-0.0023-0.01660.53360.03720.06980.48920.04220.464-9.4363-28.06651.8343
44.8569-0.43331.66785.5732-2.10586.5417-0.1947-1.2627-0.41151.3795-0.161-0.3611-0.35680.24180.30451.36860.13220.02691.41060.24810.836113.7622-51.29781.7627
55.94621.2076-0.09671.765-0.39124.6597-0.1354-0.7809-0.25820.76290.03640.0104-0.00240.41070.15171.10680.20930.21080.748-0.03010.5611-16.4984-16.106589.1818
62.1517-1.8858-1.29011.85231.1980.80140.2280.6440.0249-0.5343-0.19090.4202-0.6385-1.0445-0.09270.77280.2741-0.08760.98320.15070.7632-30.7014-11.477919.0572
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 20 through 674 )
2X-RAY DIFFRACTION2chain 'A' and (resid 679 through 819 )
3X-RAY DIFFRACTION3chain 'A' and (resid 820 through 1514 )
4X-RAY DIFFRACTION4chain 'A' and (resid 1515 through 1676 )
5X-RAY DIFFRACTION5chain 'C' and (resid 21 through 168 )
6X-RAY DIFFRACTION6chain 'D' and (resid 12 through 60 )

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