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- PDB-11mh: Cryo-EM Structure of Human C3 Pro-Convertase bound to the Compsta... -

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Basic information

Entry
Database: PDB / ID: 11mh
TitleCryo-EM Structure of Human C3 Pro-Convertase bound to the Compstatin Analog Cp60, TED Conformation 2
Components
  • Complement C3 beta chain
  • Complement C3b alpha' chain
  • Complement factor B
  • Compstatin Cp60
KeywordsIMMUNE SYSTEM / Complement System / C3 / Alternate Pathway / C3 Pro-Convertase / C3b / Factor B / Compstatin
Function / homology
Function and homology information


alternative-complement-pathway C3/C5 convertase / complement binding / C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / Alternative complement activation / complement-mediated synapse pruning ...alternative-complement-pathway C3/C5 convertase / complement binding / C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / Alternative complement activation / complement-mediated synapse pruning / positive regulation of type IIa hypersensitivity / Activation of C3 and C5 / positive regulation of lipid storage / complement activation, GZMK pathway / positive regulation of phagocytosis, engulfment / positive regulation of G protein-coupled receptor signaling pathway / symbiont cell surface / complement-dependent cytotoxicity / positive regulation of D-glucose transmembrane transport / complement receptor mediated signaling pathway / complement activation, alternative pathway / complement activation / endopeptidase inhibitor activity / neuron remodeling / amyloid-beta clearance / B cell activation / complement activation, classical pathway / positive regulation of vascular endothelial growth factor production / Purinergic signaling in leishmaniasis infection / Regulation of Complement cascade / Peptide ligand-binding receptors / response to bacterium / Post-translational protein phosphorylation / fatty acid metabolic process / positive regulation of receptor-mediated endocytosis / positive regulation of protein phosphorylation / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / positive regulation of angiogenesis / azurophil granule lumen / secretory granule lumen / blood microparticle / G alpha (i) signalling events / immune response / endoplasmic reticulum lumen / G protein-coupled receptor signaling pathway / inflammatory response / receptor ligand activity / signaling receptor binding / serine-type endopeptidase activity / Neutrophil degranulation / cell surface / signal transduction / protein-containing complex / proteolysis / : / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Complement factor B / Complement B/C2 / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Alpha-2-macroglobulin, conserved site ...Complement factor B / Complement B/C2 / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Anaphylatoxin, complement system domain / : / Alpha-macro-globulin thiol-ester bond-forming region / 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 / 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 / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / von Willebrand factor type A domain / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / VWFA domain profile. / von Willebrand factor (vWF) type A domain / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Immunoglobulin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
NICKEL (II) ION / Complement factor B / Complement C3
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsHerbine, K. / Lambris, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
Citation
Journal: J Med Chem / Year: 2026
Title: New Analogs of the Compstatin Family of Clinical Complement Inhibitors with Low Picomolar Target Affinity.
Authors: Stephanie A Vogt / Alexander J Lander / Karl Herbine / Ekaterina Umnyakova / Jannes Felsch / Roman Aschwanden / Sarah E Hughes / Oliver Schwardt / Markus A Lill / Martin Smieško / John D ...Authors: Stephanie A Vogt / Alexander J Lander / Karl Herbine / Ekaterina Umnyakova / Jannes Felsch / Roman Aschwanden / Sarah E Hughes / Oliver Schwardt / Markus A Lill / Martin Smieško / John D Lambris / Christina Lamers / Daniel Ricklin /
Abstract: Compstatin-class macrocyclic peptides have emerged as therapeutic complement modulators, with a PEGylated compstatin derivative being approved and sequence-optimized analogs with enhanced PK/PD ...Compstatin-class macrocyclic peptides have emerged as therapeutic complement modulators, with a PEGylated compstatin derivative being approved and sequence-optimized analogs with enhanced PK/PD properties showing clinical promise. By extending structure-activity relationship studies of compstatin, we identified a modification (V3I) that enhances the target affinity up to 30-fold. Analog Cp01-V3I represents the most potent proteinogenic compstatin ( = 20 nM), opening paths toward recombinant applications. Introducing the V3I modification into late-generation compstatin analogs yielded a low-picomolar-affinity derivative ( = 0.08 nM), termed Cp60, featuring potent complement inhibition in vitro. Cryogenic electron microscopy of the C3bB-Cp60 complex at 2.88 Å resolution confirmed the structural basis for enhanced target affinity and provided mechanistic insights. Lastly, we demonstrate that Cp60s ultralong target residence time enables diagnostic applications for detecting complement opsonins on biosurfaces. Collectively, this work highlights the importance of rigorous optimization of de novo peptide inhibitors to improve PK/PD properties and enable novel applications.
#1: Journal: To Be Published
Title: New analogs of the compstatin family of clinical complement inhibi-tors with low picomolar target affinity
Authors: Herbine, K. / Lambris, J.
History
DepositionMar 4, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Complement C3 beta chain
B: Complement C3b alpha' chain
C: Compstatin Cp60
D: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)261,84810
Polymers260,6434
Non-polymers1,2056
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 3 types, 3 molecules ABD

#1: Protein Complement C3 beta chain


Mass: 71393.320 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P01024
#2: Protein Complement C3b alpha' chain


Mass: 104073.164 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P01024
#4: Protein Complement factor B / C3/C5 convertase / Glycine-rich beta glycoprotein / GBG / PBF2 / Properdin factor B


Mass: 83109.750 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
References: UniProt: P00751, alternative-complement-pathway C3/C5 convertase

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Protein/peptide / Non-polymers , 2 types, 3 molecules C

#3: Protein/peptide Compstatin Cp60


Mass: 2066.493 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: Chemical ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ni / Feature type: SUBJECT OF INVESTIGATION

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Sugars , 2 types, 4 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestY
Has protein modificationY

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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: Cryo-EM Structure of Human C3 Pro-Convertase bound to the Compstatin Analog Cp60, TED Conformation 2
Type: COMPLEX / Entity ID: #1-#4 / Source: NATURAL
Molecular weightValue: 0.256 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Details: 20 mM Tris-HCl pH 7.5, 140 mM NaCl, and 10 mM NiCl2
SpecimenConc.: 0.67 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: 3 uM C3b and FB were mixed with Cp60 at 1:1:2 molar ratio in buffer containing 20 mM Tris-HCl pH 7.5, 140 mM NaCl, and 10 mM NiCl2, and incubated on ice for 1 hour prior to vitrification.
Specimen supportDetails: Negatively glow-discharged with 15 mA for 60 seconds using a PELCO EasiGlow
Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2100 nm / Nominal defocus min: 300 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 6 sec. / Electron dose: 43.36 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of real images: 6993
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 20 eV
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.7.1particle selection
2EPU3.14image acquisition
4cryoSPARC4.7.1CTF correction
7Coot0.9.8.96model fitting
9PHENIX1.21.2_5419model refinement
10cryoSPARC4.7.1initial Euler assignment
11cryoSPARC4.7.1final Euler assignment
12cryoSPARC4.7.1classification
13cryoSPARC4.7.13D reconstruction
CTF correctionDetails: Patch CTF estimation / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1475831
Details: Automated particle picking (Blob and Template picker, CryoSPARC) with manual inspection and micrograph junk detector
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 119822 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL / Target criteria: Cross-correlation coefficient
Details: Initial docking of starting model performed in ChimeraX. Flexible/Refinement performed with Phenix Real-Space Refinement. Coot used for manual fitting and inspection.
Atomic model buildingPDB-ID: 2XWJ

2xwj


Accession code: 2XWJ / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00418455
ELECTRON MICROSCOPYf_angle_d0.81725012
ELECTRON MICROSCOPYf_dihedral_angle_d9.1322872
ELECTRON MICROSCOPYf_chiral_restr0.0482798
ELECTRON MICROSCOPYf_plane_restr0.0053234

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