7BAG

C3b in complex with CP40


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


This is version 2.1 of the entry. See complete history


Literature

Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors.

Lamers, C.Xue, X.Smiesko, M.van Son, H.Wagner, B.Berger, N.Sfyroera, G.Gros, P.Lambris, J.D.Ricklin, D.

(2022) Nat Commun 13: 5519-5519

  • DOI: https://doi.org/10.1038/s41467-022-33003-7
  • Primary Citation of Related Structures:  
    7BAG

  • PubMed Abstract: 

    With the addition of the compstatin-based complement C3 inhibitor pegcetacoplan, another class of complement targeted therapeutics have recently been approved. Moreover, compstatin derivatives with enhanced pharmacodynamic and pharmacokinetic profiles are in clinical development (e.g., Cp40/AMY-101). Despite this progress, the target binding and inhibitory modes of the compstatin family remain incompletely described. Here, we present the crystal structure of Cp40 complexed with its target C3b at 2.0-Å resolution. Structure-activity-relationship studies rationalize the picomolar affinity and long target residence achieved by lead optimization, and reveal a role for structural water in inhibitor binding. We provide explanations for the narrow species specificity of this drug class and demonstrate distinct target selection modes between clinical compstatin derivatives. Functional studies provide further insight into physiological complement activation and corroborate the mechanism of its compstatin-mediated inhibition. Our study may thereby guide the application of existing and development of next-generation compstatin analogs.


  • Organizational Affiliation

    Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Complement C3645Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P01024 (Homo sapiens)
Explore P01024 
Go to UniProtKB:  P01024
PHAROS:  P01024
GTEx:  ENSG00000125730 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01024
Glycosylation
Glycosylation Sites: 1Go to GlyGen: P01024-1
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Complement C3915Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P01024 (Homo sapiens)
Explore P01024 
Go to UniProtKB:  P01024
PHAROS:  P01024
GTEx:  ENSG00000125730 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01024
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Compstatin CP4014synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
D
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PEG
Query on PEG

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
I [auth B],
J [auth B],
K [auth B]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
ACM
Query on ACM

Download Ideal Coordinates CCD File 
H [auth B]ACETAMIDE
C2 H5 N O
DLFVBJFMPXGRIB-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
E [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
NH2
Query on NH2

Download Ideal Coordinates CCD File 
L [auth C]AMINO GROUP
H2 N
QGZKDVFQNNGYKY-UHFFFAOYSA-N
Modified Residues  3 Unique
IDChains TypeFormula2D DiagramParent
EXL
Query on EXL
C
L-PEPTIDE LINKINGC12 H14 N2 O2TRP
IML
Query on IML
C
L-PEPTIDE LINKINGC7 H15 N O2ILE
SAR
Query on SAR
C
PEPTIDE LINKINGC3 H7 N O2GLY
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.508α = 90
b = 90.528β = 108.84
c = 140.093γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Swiss National Science FoundationSwitzerland31003A_176104
Netherlands Organisation for Scientific Research (NWO)Netherlands700.54.304
European Research Council (ERC)Netherlands233229
European Communitys Seventh Framework ProgrammeNetherlands283570

Revision History  (Full details and data files)

  • Version 1.0: 2022-01-12
    Type: Initial release
  • Version 1.1: 2023-03-01
    Changes: Database references
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Derived calculations
  • Version 2.1: 2024-02-07
    Changes: Refinement description