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- PDB-7anq: Complete PCSK9 C-ter domain in complex with VHH P1.40 -

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Basic information

Entry
Database: PDB / ID: 7anq
TitleComplete PCSK9 C-ter domain in complex with VHH P1.40
Components
  • Proprotein convertase subtilisin/kexin type 9PCSK9
  • VHH P1.40 minibody anti-Cter PCSK9
KeywordsHYDROLASE / PCSK9 / VHH P1.40 / complex
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)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsCiccone, L. / Legrand, P. / Stura, E.A. / Dive, V. / Seidahn, N.G. / Fruchart Gaillard, C.
CitationJournal: Mol Metab / Year: 2022
Title: Molecular interactions of PCSK9 with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation of LDLR levels.
Authors: Fruchart Gaillard, C. / Ouadda, A.B.D. / Ciccone, L. / Girard, E. / Mikaeeli, S. / Evagelidis, A. / Le Devehat, M. / Susan-Resiga, D. / Lajeunesse, E.C. / Nozach, H. / Ramos, O.H.P. / ...Authors: Fruchart Gaillard, C. / Ouadda, A.B.D. / Ciccone, L. / Girard, E. / Mikaeeli, S. / Evagelidis, A. / Le Devehat, M. / Susan-Resiga, D. / Lajeunesse, E.C. / Nozach, H. / Ramos, O.H.P. / Thureau, A. / Legrand, P. / Prat, A. / Dive, V. / Seidah, N.G.
History
DepositionOct 12, 2020Deposition site: PDBE / Processing site: PDBE
SupersessionOct 20, 2021ID: 6F5G
Revision 1.0Oct 20, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2023Group: 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
Revision 1.2Feb 7, 2024Group: 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

Downloads & links

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Assembly

Deposited unit
A: Proprotein convertase subtilisin/kexin type 9
B: VHH P1.40 minibody anti-Cter PCSK9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5244
Polymers38,8582
Non-polymers6672
Water2,054114
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2650 Å2
ΔGint-12 kcal/mol
Surface area16380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.430, 52.430, 263.410
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: 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: 24518.785 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: Antibody VHH P1.40 minibody anti-Cter PCSK9


Mass: 14338.765 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 114 / 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: 2.39 Å3/Da / Density % sol: 48.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Protein: Purified PCSK9/P1.40 complex at 5.3 mg/ml Precipitant: 10% PEG 4.000, 0.2M imidazole malate, pH 7.0 Cryoprotectant: 40% SM3 (25 % diethylene glycol + 25 % ethylene glycol + 25 % ...Details: Protein: Purified PCSK9/P1.40 complex at 5.3 mg/ml Precipitant: 10% PEG 4.000, 0.2M imidazole malate, pH 7.0 Cryoprotectant: 40% SM3 (25 % diethylene glycol + 25 % ethylene glycol + 25 % glycerol + 25 % 1,4-dioxane) 25% PEG 4.000, 0.2M imidazole malate, pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 12, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.196→48.7 Å / Num. obs: 19768 / % possible obs: 99.7 % / Redundancy: 11.5 % / CC1/2: 0.995 / Net I/σ(I): 7.79
Reflection shellResolution: 2.196→2.33 Å / Num. unique obs: 63927 / CC1/2: 0.275

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
MOLREPmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3H42, 4EIZ

3h42

4eiz


Resolution: 2.2→28.32 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.906 / SU R Cruickshank DPI: 0.269 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.298 / SU Rfree Blow DPI: 0.219 / SU Rfree Cruickshank DPI: 0.212
RfactorNum. reflection% reflectionSelection details
Rfree0.256 988 5 %RANDOM
Rwork0.213 ---
obs0.215 19758 100 %-
Displacement parametersBiso max: 150.12 Å2 / Biso mean: 52.02 Å2 / Biso min: 25.75 Å2
Baniso -1Baniso -2Baniso -3
1--0.0476 Å20 Å20 Å2
2---0.0476 Å20 Å2
3---0.0952 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.2→28.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2644 0 43 114 2801
Biso mean--111.1 49.15 -
Num. residues----349
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d943SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes477HARMONIC5
X-RAY DIFFRACTIONt_it2775HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion364SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3027SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2775HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3774HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.27
X-RAY DIFFRACTIONt_other_torsion21.34
LS refinement shellResolution: 2.2→2.22 Å / Rfactor Rfree error: 0 / Total num. of bins used: 49
RfactorNum. reflection% reflection
Rfree0.3348 20 4.95 %
Rwork0.2387 384 -
all0.2436 404 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -0.5648 Å / Origin y: 18.5492 Å / Origin z: -9.5339 Å
111213212223313233
T-0.0426 Å2-0.0378 Å2-0.0026 Å2--0.0263 Å2-0.0055 Å2--0.001 Å2
L1.6107 °2-0.2297 °2-0.5003 °2-1.0384 °20.3403 °2--1.3032 °2
S0.0227 Å °0.1018 Å °-0.0127 Å °-0.035 Å °-0.0186 Å °0.0214 Å °-0.0064 Å °-0.047 Å °-0.0041 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ *|* }A452 - 682
2X-RAY DIFFRACTION1{ *|* }A452 - 682
3X-RAY DIFFRACTION1{ *|* }B452 - 682
4X-RAY DIFFRACTION1{ *|* }S452 - 682

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