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- PDB-8fvm: PCSK9 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 8fvm
TitlePCSK9 in complex with an inhibitor
Components
  • (Proprotein convertase subtilisin/kexin type 9) x 2
  • DGN-DVA-YC3-GLU-PRO-THR-THR-PHE-MAA-A1BC0 inhibitor
KeywordsHYDROLASE/INHIBITOR / complex / inhibitor / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


low-density lipoprotein particle receptor catabolic process / : / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / extrinsic component of external side of plasma membrane / PCSK9-LDLR complex / PCSK9-AnxA2 complex / : / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding ...low-density lipoprotein particle receptor catabolic process / : / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / extrinsic component of external side of plasma membrane / PCSK9-LDLR complex / PCSK9-AnxA2 complex / : / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding / negative regulation of low-density lipoprotein particle clearance / low-density lipoprotein particle binding / positive regulation of low-density lipoprotein particle receptor catabolic process / LDL clearance / lipoprotein metabolic process / very-low-density lipoprotein particle receptor binding / negative regulation of receptor internalization / : / regulation of signaling receptor activity / endolysosome membrane / sodium channel inhibitor activity / signaling receptor inhibitor activity / lysosomal transport / triglyceride metabolic process / low-density lipoprotein particle receptor binding / COPII-coated ER to Golgi transport vesicle / protein autoprocessing / positive regulation of receptor internalization / apolipoprotein binding / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / regulation of neuron apoptotic process / phospholipid metabolic process / neurogenesis / cholesterol metabolic process / VLDLR internalisation and degradation / cholesterol homeostasis / liver development / cellular response to starvation / kidney development / Post-translational protein phosphorylation / cellular response to insulin stimulus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron differentiation / positive regulation of neuron apoptotic process / late endosome / early endosome / lysosome / endoplasmic reticulum lumen / lysosomal membrane / serine-type endopeptidase activity / apoptotic process / perinuclear region of cytoplasm / cell surface / endoplasmic reticulum / Golgi apparatus / extracellular space / RNA binding / extracellular region / plasma membrane / cytoplasm
Similarity search - Function
Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proteinase K-like catalytic domain / Peptidase S8 propeptide/proteinase inhibitor I9 / Peptidase inhibitor I9 / Peptidase S8 propeptide/proteinase inhibitor I9 superfamily ...Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proteinase K-like catalytic domain / Peptidase S8 propeptide/proteinase inhibitor I9 / Peptidase inhibitor I9 / Peptidase S8 propeptide/proteinase inhibitor I9 superfamily / : / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain
Similarity search - Domain/homology
: / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.852 Å
AuthorsXu, M. / Chopra, R.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Chemmedchem / Year: 2024
Title: Discovery of Truncated Cyclic Peptides Targeting an Induced-Fit Pocket on PCSK9.
Authors: Grosche, P. / Flyer, A.N. / Gattlen, R. / Xu, M. / Golosov, A.A. / Vera, V. / Pickett, S. / Brousseau, M.E. / Chopra, R. / Clairmont, K.B. / Koch, A. / Liu, E. / Reid, P. / Perry, L. / Yang, ...Authors: Grosche, P. / Flyer, A.N. / Gattlen, R. / Xu, M. / Golosov, A.A. / Vera, V. / Pickett, S. / Brousseau, M.E. / Chopra, R. / Clairmont, K.B. / Koch, A. / Liu, E. / Reid, P. / Perry, L. / Yang, L. / Yang, Q. / Monovich, L.G.
History
DepositionJan 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Proprotein convertase subtilisin/kexin type 9
B: Proprotein convertase subtilisin/kexin type 9
C: DGN-DVA-YC3-GLU-PRO-THR-THR-PHE-MAA-A1BC0 inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8254
Polymers75,7853
Non-polymers401
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4200 Å2
ΔGint-37 kcal/mol
Surface area23490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.474, 70.730, 148.190
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Proprotein convertase subtilisin/kexin type 9 / Neural apoptosis-regulated convertase 1 / NARC-1 / Proprotein convertase 9 / PC9 / Subtilisin/kexin- ...Neural apoptosis-regulated convertase 1 / NARC-1 / Proprotein convertase 9 / PC9 / Subtilisin/kexin-like protease PC9


Mass: 17035.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PCSK9, NARC1, PSEC0052 / Production host: Homo sapiens (human)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Protein Proprotein convertase subtilisin/kexin type 9 / Neural apoptosis-regulated convertase 1 / NARC-1 / Proprotein convertase 9 / PC9 / Subtilisin/kexin- ...Neural apoptosis-regulated convertase 1 / NARC-1 / Proprotein convertase 9 / PC9 / Subtilisin/kexin-like protease PC9


Mass: 57443.730 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PCSK9, NARC1, PSEC0052 / Production host: Homo sapiens (human)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#3: Protein/peptide DGN-DVA-YC3-GLU-PRO-THR-THR-PHE-MAA-A1BC0 inhibitor


Type: Cyclic peptide / Class: Inhibitor / Mass: 1305.563 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: BIRD: PRD_002558
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.19 Å3/Da / Density % sol: 43.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 20.0% Peg-6000, 0.1M Tris pH8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER R 1M / Detector: PIXEL / Date: Oct 3, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.852→74.095 Å / Num. obs: 16191 / % possible obs: 100 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.15 / Net I/σ(I): 12.4
Reflection shellResolution: 2.852→2.862 Å / Rmerge(I) obs: 0.795 / Num. unique obs: 156

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1refinement
HKL-2000data reduction
FFTphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.852→48.205 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2384 779 4.83 %
Rwork0.1975 --
obs0.1996 16126 99.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.852→48.205 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4369 0 1 0 4370
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0124478
X-RAY DIFFRACTIONf_angle_d1.5796062
X-RAY DIFFRACTIONf_dihedral_angle_d17.521591
X-RAY DIFFRACTIONf_chiral_restr0.092693
X-RAY DIFFRACTIONf_plane_restr0.009790
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.852-3.03070.35441210.27042523X-RAY DIFFRACTION100
3.0307-3.26460.29031350.22642498X-RAY DIFFRACTION100
3.2646-3.59310.25521300.19972531X-RAY DIFFRACTION100
3.5931-4.11270.21181160.18632555X-RAY DIFFRACTION100
4.1127-5.18070.2061250.17232564X-RAY DIFFRACTION99
5.1807-48.2050.22661520.19512676X-RAY DIFFRACTION100

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