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- PDB-5iec: Structural basis for therapeutic inhibition of complement C5 -

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Basic information

Entry
Database: PDB / ID: 5iec
TitleStructural basis for therapeutic inhibition of complement C5
ComponentsRaCI2
KeywordsBLOOD CLOTTING / complement inhibitor / RaCI / STRUCTURE FROM CYANA 3.96
Function / homologytoxin activity / extracellular region / Complement inhibitor RaCI2
Function and homology information
Biological speciesRhipicephalus appendiculatus (arthropod)
MethodSOLUTION NMR
AuthorsSheppard, D. / Lea, S.M.
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 25, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 27, 2016Provider: repository / Type: Initial release
Revision 1.1May 11, 2016Group: Database references
Revision 1.2Feb 7, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3May 8, 2019Group: Data collection / Category: pdbx_nmr_software / Item: _pdbx_nmr_software.name
Revision 1.4Nov 20, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_nmr_spectrometer / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_nmr_spectrometer.model / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RaCI2


Theoretical massNumber of molelcules
Total (without water)7,4761
Polymers7,4761
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area5690 Å2
MethodPISA
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / -
Representative

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Components

#1: Protein RaCI2


Mass: 7476.488 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rhipicephalus appendiculatus (arthropod)
Production host: Escherichia coli (E. coli) / References: UniProt: A0A182DWE4*PLUS
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic13D 1H-13C NOESY aliphatic
121isotropic13D 1H-15N NOESY
131isotropic13D CBCA(CO)NH
141isotropic13D CBCANH
151isotropic13D HNCO
161isotropic13D (H)CCH-TOCSY
171isotropic13D HNCA
181isotropic13D HN(CO)CA
191isotropic13D HBHA(CO)NH
1101isotropic13D CC(CO)NH
1111isotropic13D HNHA

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Sample preparation

DetailsType: solution
Contents: 330 uM [U-100% 13C] [U-100% 15N] RaCI2, 90% H2O/10% D2O
Label: 15N 13C sample 1 / Solvent system: 90% H2O/10% D2O
SampleConc.: 330 uM / Component: RaCI2 / Isotopic labeling: [U-100% 13C; U-100% 15N]
Sample conditionsIonic strength: 162.7 mM / Label: conditions_1 / pH: 7.4 / Pressure: 1 atm / Temperature: 298 K

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NMR measurement

NMR spectrometerType: Bruker AVANCE II / Manufacturer: Bruker / Model: AVANCE II / Field strength: 500 MHz

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Processing

NMR software
NameVersionDeveloperClassification
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
SparkyGoddardpeak picking
SparkyGoddardchemical shift assignment
CS-ROSETTAShen, Vernon, Baker and Baxstructure calculation
CYANA3.97Guntert, Mumenthaler and Wuthrichstructure calculation
NMR ensembleConformers submitted total number: 10

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