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

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Basic information

Entry
Database: PDB / ID: 8fpq
TitlePCSK9 in complex with an inhibitor
Components
  • (Proprotein convertase subtilisin/kexin type 9) x 2
  • MCR-PHE-VAL-PRO-THR-THR-BIF-MAA-BIF-MAA-GLU-ALA-PRO-ALA-NEH 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 / negative regulation of sodium ion import across 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 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 / negative regulation of sodium ion import across 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 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 / COPII-coated ER to Golgi transport vesicle / endolysosome membrane / sodium channel inhibitor activity / negative regulation of low-density lipoprotein particle clearance / signaling receptor inhibitor activity / lysosomal transport / triglyceride metabolic process / low-density lipoprotein particle receptor binding / protein autoprocessing / positive regulation of receptor internalization / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / apolipoprotein binding / cholesterol metabolic process / regulation of neuron apoptotic process / phospholipid metabolic process / neurogenesis / VLDLR internalisation and degradation / cholesterol homeostasis / cellular response to starvation / Post-translational protein phosphorylation / kidney development / liver development / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to insulin stimulus / neuron differentiation / late endosome / positive regulation of neuron apoptotic process / 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: 2.503 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 5, 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
L: MCR-PHE-VAL-PRO-THR-THR-BIF-MAA-BIF-MAA-GLU-ALA-PRO-ALA-NEH inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,4454
Polymers68,4053
Non-polymers401
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4750 Å2
ΔGint-33 kcal/mol
Surface area23400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.414, 70.369, 150.829
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: 10490.109 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: 56264.477 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 MCR-PHE-VAL-PRO-THR-THR-BIF-MAA-BIF-MAA-GLU-ALA-PRO-ALA-NEH inhibitor


Type: Cyclic peptide / Class: Inhibitor / Mass: 1649.946 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: BIRD: PRD_002519
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / Source method: isolated from a natural source / Formula: H2O
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: 2.42 Å3/Da / Density % sol: 49.2 %
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: Nov 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→150 Å / Num. obs: 140840 / % possible obs: 99.1 % / Redundancy: 6.3 % / Rmerge(I) obs: 0.17 / Net I/σ(I): 11.7
Reflection shellResolution: 2.5→2.512 Å / Rmerge(I) obs: 1.299 / Num. unique obs: 14084

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1refinement
HKL-2000data reduction
FFTphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.503→57.671 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2344 1215 5.16 %
Rwork0.1884 --
obs0.1907 23564 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.503→57.671 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4366 0 1 52 4419
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0114480
X-RAY DIFFRACTIONf_angle_d1.6366065
X-RAY DIFFRACTIONf_dihedral_angle_d17.3541588
X-RAY DIFFRACTIONf_chiral_restr0.081697
X-RAY DIFFRACTIONf_plane_restr0.009789
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5033-2.60360.28141500.23422426X-RAY DIFFRACTION100
2.6036-2.7220.29091230.2262436X-RAY DIFFRACTION100
2.722-2.86560.25141290.21312448X-RAY DIFFRACTION100
2.8656-3.04510.28481260.21632453X-RAY DIFFRACTION100
3.0451-3.28020.26941320.20052473X-RAY DIFFRACTION100
3.2802-3.61020.23261480.18992447X-RAY DIFFRACTION100
3.6102-4.13250.20811330.17772500X-RAY DIFFRACTION100
4.1325-5.2060.19561470.15592518X-RAY DIFFRACTION100
5.206-57.6710.22421270.18052648X-RAY DIFFRACTION100

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