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- PDB-7kfa: PCSK9 in complex with PCSK9i a 13mer cyclic peptide LDLR disruptor -

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Basic information

Entry
Database: PDB / ID: 7kfa
TitlePCSK9 in complex with PCSK9i a 13mer cyclic peptide LDLR disruptor
Components
  • 1-[2,6,10.14-TETRAMETHYL-HEXADECAN-16-YL]-2-[2,10,14-TRIMETHYLHEXADECAN-16-YL]GLYCEROL
  • Proprotein convertase subtilisin/kexin type 9 Propeptide
  • Proprotein convertase subtilisin/kexin type 9PCSK9
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: 2.45 Å
AuthorsChopra, R. / Xu, M. / Spraggon, G.
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 13, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 24, 2021Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year
Revision 1.3Oct 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
D: 1-[2,6,10.14-TETRAMETHYL-HEXADECAN-16-YL]-2-[2,10,14-TRIMETHYLHEXADECAN-16-YL]GLYCEROL
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,9664
Polymers73,9263
Non-polymers401
Water1,78399
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4690 Å2
ΔGint-39 kcal/mol
Surface area23470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.422, 70.338, 150.623
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 1-[2,6,10.14-TETRAMETHYL-HEXADECAN-16-YL]-2-[2,10,14-TRIMETHYLHEXADECAN-16-YL]GLYCEROL


Mass: 1633.948 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
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 99 / 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: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / 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: 2.45→57.67 Å / Num. obs: 23342 / % possible obs: 94.2 % / Redundancy: 3.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.082 / Rpim(I) all: 0.096 / Rrim(I) all: 0.096 / Net I/σ(I): 10.6
Reflection shellResolution: 2.45→2.58 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.555 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 3405 / CC1/2: 0.784 / Rpim(I) all: 0.335 / Rrim(I) all: 0.665 / % possible all: 78.4

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.4data scaling
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.25data extraction
FFTphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2QTW

2qtw


Resolution: 2.45→57.67 Å / SU ML: 0.2931 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.7678
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2417 1193 5.12 %
Rwork0.1892 22128 -
obs0.1919 23321 93.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51.55 Å2
Refinement stepCycle: LAST / Resolution: 2.45→57.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4237 0 119 99 4455
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00534445
X-RAY DIFFRACTIONf_angle_d0.82376032
X-RAY DIFFRACTIONf_chiral_restr0.0504694
X-RAY DIFFRACTIONf_plane_restr0.0047784
X-RAY DIFFRACTIONf_dihedral_angle_d23.1173620
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.45-2.550.31631370.25152454X-RAY DIFFRACTION94.67
2.55-2.670.32351460.23752463X-RAY DIFFRACTION95.25
2.67-2.810.27891230.22552489X-RAY DIFFRACTION94.88
2.81-2.980.23631210.2172480X-RAY DIFFRACTION94.82
2.98-3.210.25061250.19872445X-RAY DIFFRACTION93.49
3.21-3.540.30081440.18462445X-RAY DIFFRACTION93.4
3.54-4.050.23421390.17572438X-RAY DIFFRACTION92.5
4.05-5.10.17651430.15652439X-RAY DIFFRACTION91.46
5.1-57.670.23361150.18962475X-RAY DIFFRACTION87.41

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