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- PDB-3h42: Crystal structure of PCSK9 in complex with Fab from LDLR competit... -

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Basic information

Entry
Database: PDB / ID: 3h42
TitleCrystal structure of PCSK9 in complex with Fab from LDLR competitive antibody
Components
  • (Fab from LDLR competitive antibody: ...Fragment antigen-binding) x 2
  • (Proprotein convertase subtilisin/kexin type ...) x 2
KeywordsHYDROLASE/IMMUNE SYSTEM / Hydrolase / Protein Fab Complex / Autocatalytic cleavage / Cholesterol metabolism / Disease mutation / Disulfide bond / Glycoprotein / Lipid metabolism / Phosphoprotein / Protease / Secreted / Serine protease / Steroid metabolism / Zymogen / HYDROLASE-IMMUNE SYSTEM 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 / 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 / Peptidase S8 propeptide/proteinase inhibitor I9 / Proteinase K-like catalytic domain / Peptidase S8/S53 domain ...Proprotein convertase subtilisin/kexin type 9 / 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 / Peptidase S8 propeptide/proteinase inhibitor I9 / Proteinase K-like catalytic domain / Peptidase S8/S53 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 / Jelly Rolls / Alpha-Beta Plaits / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsPiper, D.E. / Walker, N.P.C. / Romanow, W.G. / Thibault, S.T. / Tsai, M.M. / Yang, E.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2009
Title: From the Cover: A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
Authors: Chan, J.C. / Piper, D.E. / Cao, Q. / Liu, D. / King, C. / Wang, W. / Tang, J. / Liu, Q. / Higbee, J. / Xia, Z. / Di, Y. / Shetterly, S. / Arimura, Z. / Salomonis, H. / Romanow, W.G. / ...Authors: Chan, J.C. / Piper, D.E. / Cao, Q. / Liu, D. / King, C. / Wang, W. / Tang, J. / Liu, Q. / Higbee, J. / Xia, Z. / Di, Y. / Shetterly, S. / Arimura, Z. / Salomonis, H. / Romanow, W.G. / Thibault, S.T. / Zhang, R. / Cao, P. / Yang, X.P. / Yu, T. / Lu, M. / Retter, M.W. / Kwon, G. / Henne, K. / Pan, O. / Tsai, M.M. / Fuchslocher, B. / Yang, E. / Zhou, L. / Lee, K.J. / Daris, M. / Sheng, J. / Wang, Y. / Shen, W.D. / Yeh, W.C. / Emery, M. / Walker, N.P. / Shan, B. / Schwarz, M. / Jackson, S.M.
History
DepositionApr 17, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Sep 6, 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
B: Proprotein convertase subtilisin/kexin type 9
L: Fab from LDLR competitive antibody: Light chain
H: Fab from LDLR competitive antibody: Heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,5765
Polymers119,5534
Non-polymers231
Water10,233568
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8230 Å2
ΔGint-49.1 kcal/mol
Surface area41850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)264.721, 137.352, 69.885
Angle α, β, γ (deg.)90.000, 102.840, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Proprotein convertase subtilisin/kexin type ... , 2 types, 2 molecules AB

#1: Protein Proprotein convertase subtilisin/kexin type 9 / PCSK9 / Proprotein convertase PC9 / Subtilisin/kexin-like protease PC9 / Neural apoptosis-regulated ...Proprotein convertase PC9 / Subtilisin/kexin-like protease PC9 / Neural apoptosis-regulated convertase 1 / NARC-1


Mass: 14107.839 Da / Num. of mol.: 1 / Fragment: UNP residues 31-152
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NARC1, PCSK9, PSEC0052 / Cell line (production host): Hi-Five / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Protein Proprotein convertase subtilisin/kexin type 9 / PCSK9 / Proprotein convertase PC9 / Subtilisin/kexin-like protease PC9 / Neural apoptosis-regulated ...Proprotein convertase PC9 / Subtilisin/kexin-like protease PC9 / Neural apoptosis-regulated convertase 1 / NARC-1


Mass: 57328.645 Da / Num. of mol.: 1 / Fragment: UNP residues 153-692 / Mutation: N533A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NARC1, PCSK9, PSEC0052 / Cell line (production host): Hi-Five / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases

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Antibody , 2 types, 2 molecules LH

#3: Antibody Fab from LDLR competitive antibody: Light chain / Fragment antigen-binding


Mass: 22626.869 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Antibody Fab from LDLR competitive antibody: Heavy chain / Fragment antigen-binding


Mass: 25489.293 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)

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Non-polymers , 2 types, 569 molecules

#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 568 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsAUTHORS STATE THAT RESIDUE GLY B 620 IS A MUTATION THAT WAS LIKELY INTRODUCED DURING CLONING.

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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: 5.18 Å3/Da / Density % sol: 76.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.3
Details: 0.1 M Tris-HCl, 0.2 M Sodium acetate, 10-15% PEG 4000, 3-6% Dextran sodium salt (Mr 5000), pH 8.3, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationMonochromator: Si(111) Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→40 Å / Num. all: 107766 / Num. obs: 107766 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.5 % / Biso Wilson estimate: 42.3 Å2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 11
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.589 / Mean I/σ(I) obs: 2.5 / Num. unique all: 15651 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
CNSrefinement
PDB_EXTRACT3.005data extraction
ADSCQuantumdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2PMW

2pmw


Resolution: 2.3→40 Å / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.209 5376 -Random
Rwork0.191 ---
all0.192 107765 --
obs0.192 107765 99.9 %-
Displacement parametersBiso max: 117.99 Å2 / Biso mean: 46.497 Å2 / Biso min: 18.25 Å2
Refinement stepCycle: LAST / Resolution: 2.3→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7627 0 1 568 8196
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg0.852
LS refinement shellResolution: 2.3→2.32 Å
RfactorNum. reflection
Rfree0.312 104
Rwork0.29 -
obs-1983

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