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- PDB-7kev: PCSK9 in complex with a cyclic peptide LDLR disruptor -

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Basic information

Entry
Database: PDB / ID: 7kev
TitlePCSK9 in complex with a cyclic peptide LDLR disruptor
Components
  • Proprotein convertase subtilisin/kexin type 9 Propeptide
  • Proprotein convertase subtilisin/kexin type 9PCSK9
  • cyclic peptide LDLR disruptor
KeywordsLIPID TRANSPORT / HYDROLASE / PRO-PROTEIN CONVERTASE / CORONARY HEART DISEASE / HYPERCHOLESTEROLEMIA / LOW DENSITY LIPOPROTEIN RECEPTOR / AUTOCATALYTIC CLEAVAGE / CHOLESTEROL METABOLISM / DISEASE MUTATION / GLYCOPROTEIN / LIPID METABOLISM / PHOSPHORYLATION / PROTEASE / SECRETED / SERINE PROTEASE / STEROID METABOLISM / ZYMOGEN
Function / homology
Function and homology information


negative regulation of low-density lipoprotein particle receptor binding / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / low-density lipoprotein particle receptor catabolic process / extrinsic component of external side of plasma membrane / very-low-density lipoprotein particle binding / PCSK9-LDLR complex / negative regulation of receptor recycling / PCSK9-AnxA2 complex / negative regulation of sodium ion transmembrane transporter activity / apolipoprotein receptor binding ...negative regulation of low-density lipoprotein particle receptor binding / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / low-density lipoprotein particle receptor catabolic process / extrinsic component of external side of plasma membrane / very-low-density lipoprotein particle binding / PCSK9-LDLR complex / negative regulation of receptor recycling / PCSK9-AnxA2 complex / negative regulation of sodium ion transmembrane transporter activity / apolipoprotein receptor binding / negative regulation of low-density lipoprotein particle clearance / low-density lipoprotein particle binding / LDL clearance / positive regulation of low-density lipoprotein particle receptor catabolic process / lipoprotein metabolic process / signaling receptor inhibitor activity / very-low-density lipoprotein particle receptor binding / negative regulation of low-density lipoprotein receptor activity / negative regulation of receptor internalization / endolysosome membrane / regulation of signaling receptor activity / sodium channel inhibitor activity / lysosomal transport / triglyceride metabolic process / low-density lipoprotein particle receptor binding / COPII-coated ER to Golgi transport vesicle / apolipoprotein binding / positive regulation of receptor internalization / protein autoprocessing / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / phospholipid metabolic process / regulation of neuron apoptotic process / VLDLR internalisation and degradation / cellular response to starvation / cholesterol metabolic process / neurogenesis / liver development / cholesterol homeostasis / kidney development / Post-translational protein phosphorylation / neuron differentiation / cellular response to insulin stimulus / positive regulation of neuron apoptotic process / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / : / late endosome / lysosome / early endosome / lysosomal membrane / endoplasmic reticulum lumen / serine-type endopeptidase activity / apoptotic process / perinuclear region of cytoplasm / Golgi apparatus / cell surface / endoplasmic reticulum / 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 / Serine proteases, subtilase domain profile. / Peptidase S8, subtilisin-related / 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 / FOURIER SYNTHESIS / Resolution: 2.8 Å
AuthorsSpraggon, G. / Chopra, R.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: Cell Chem Biol / Year: 2022
Title: Identification of a PCSK9-LDLR disruptor peptide with in vivo function.
Authors: Brousseau, M.E. / Clairmont, K.B. / Spraggon, G. / Flyer, A.N. / Golosov, A.A. / Grosche, P. / Amin, J. / Andre, J. / Burdick, D. / Caplan, S. / Chen, G. / Chopra, R. / Ames, L. / Dubiel, D. ...Authors: Brousseau, M.E. / Clairmont, K.B. / Spraggon, G. / Flyer, A.N. / Golosov, A.A. / Grosche, P. / Amin, J. / Andre, J. / Burdick, D. / Caplan, S. / Chen, G. / Chopra, R. / Ames, L. / Dubiel, D. / Fan, L. / Gattlen, R. / Kelly-Sullivan, D. / Koch, A.W. / Lewis, I. / Li, J. / Liu, E. / Lubicka, D. / Marzinzik, A. / Nakajima, K. / Nettleton, D. / Ottl, J. / Pan, M. / Patel, T. / Perry, L. / Pickett, S. / Poirier, J. / Reid, P.C. / Pelle, X. / Seepersaud, M. / Subramanian, V. / Vera, V. / Xu, M. / Yang, L. / Yang, Q. / Yu, J. / Zhu, G. / Monovich, L.G.
#1: Journal: Proc Natl Acad Sci U S A / Year: 2007
Title: The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain.
Authors: Hampton, E.N. / Knuth, M.W. / Li, J. / Harris, J.L. / Lesley, S.A. / Spraggon, G.
History
DepositionOct 12, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proprotein convertase subtilisin/kexin type 9 Propeptide
B: Proprotein convertase subtilisin/kexin type 9
C: cyclic peptide LDLR disruptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,0564
Polymers74,0163
Non-polymers401
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4730 Å2
ΔGint-37 kcal/mol
Surface area23180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.225, 70.441, 149.257
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Proprotein convertase subtilisin/kexin type 9 Propeptide / 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: 14019.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PCSK9, NARC1, PSEC0052 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8NBP7
#2: Protein Proprotein convertase subtilisin/kexin type 9 / PCSK9 / 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: 58272.621 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PCSK9, NARC1, PSEC0052 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#3: Protein/peptide cyclic peptide LDLR disruptor


Mass: 1723.991 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Chemical ChemComp-CA / CALCIUM ION


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


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.28 Å3/Da / Density % sol: 45.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 20.0% PEG-6000, 0.1M TRIS

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.97946 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Jan 12, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.8→74.656 Å / Num. obs: 15722 / % possible obs: 87.1 % / Redundancy: 3.8 % / Biso Wilson estimate: 54.5 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.143 / Rpim(I) all: 0.076 / Rrim(I) all: 0.164 / Net I/σ(I): 10
Reflection shellResolution: 2.818→2.828 Å / Redundancy: 3.9 % / Rmerge(I) obs: 1.25 / Num. unique obs: 153 / CC1/2: 0.516 / Rpim(I) all: 0.652 / Rrim(I) all: 0.99 / % possible all: 94.4

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACT3.25data extraction
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2QTW

2qtw


Resolution: 2.8→40.64 Å / SU ML: 0.4093 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.1903
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2804 785 4.99 %
Rwork0.2258 14937 -
obs0.2285 15722 93.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 54.88 Å2
Refinement stepCycle: LAST / Resolution: 2.8→40.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4278 0 84 17 4379
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00834446
X-RAY DIFFRACTIONf_angle_d1.01426026
X-RAY DIFFRACTIONf_chiral_restr0.0519694
X-RAY DIFFRACTIONf_plane_restr0.0059784
X-RAY DIFFRACTIONf_dihedral_angle_d16.92651593
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.980.34721190.30782451X-RAY DIFFRACTION94.31
2.98-3.210.38591380.28882495X-RAY DIFFRACTION96.24
3.21-3.530.28431390.25012478X-RAY DIFFRACTION94.96
3.53-4.040.30211160.22712501X-RAY DIFFRACTION94.37
4.04-5.090.25671370.19652479X-RAY DIFFRACTION93.26
5.09-40.640.23141360.19612533X-RAY DIFFRACTION90.51

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