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- PDB-6u38: PCSK9 in complex with a Fab and compound 8 -

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Basic information

Entry
Database: PDB / ID: 6u38
TitlePCSK9 in complex with a Fab and compound 8
Components
  • Fab Heavy ChainFragment antigen-binding
  • Fab Light ChainFragment antigen-binding
  • Proprotein convertase subtilisin/kexin type 9PCSK9
KeywordsHYDROLASE/Immune System / Serine Type Endopeptidase Activity Proteolysis / HYDROLASE / 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
Chem-PVJ / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsLu, J. / Soisson, S.
CitationJournal: Cell Chem Biol / Year: 2020
Title: From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.
Authors: Petrilli, W.L. / Adam, G.C. / Erdmann, R.S. / Abeywickrema, P. / Agnani, V. / Ai, X. / Baysarowich, J. / Byrne, N. / Caldwell, J.P. / Chang, W. / DiNunzio, E. / Feng, Z. / Ford, R. / Ha, S. ...Authors: Petrilli, W.L. / Adam, G.C. / Erdmann, R.S. / Abeywickrema, P. / Agnani, V. / Ai, X. / Baysarowich, J. / Byrne, N. / Caldwell, J.P. / Chang, W. / DiNunzio, E. / Feng, Z. / Ford, R. / Ha, S. / Huang, Y. / Hubbard, B. / Johnston, J.M. / Kavana, M. / Lisnock, J.M. / Liang, R. / Lu, J. / Lu, Z. / Meng, J. / Orth, P. / Palyha, O. / Parthasarathy, G. / Salowe, S.P. / Sharma, S. / Shipman, J. / Soisson, S.M. / Strack, A.M. / Youm, H. / Zhao, K. / Zink, D.L. / Zokian, H. / Addona, G.H. / Akinsanya, K. / Tata, J.R. / Xiong, Y. / Imbriglio, J.E.
History
DepositionAug 21, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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
H: Fab Heavy Chain
L: Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)202,7035
Polymers202,1474
Non-polymers5561
Water1,04558
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)155.033, 155.033, 151.919
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65

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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: 76081.656 Da / Num. of mol.: 2 / Mutation: V474I, G670E
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
#2: Antibody Fab Heavy Chain / Fragment antigen-binding


Mass: 26546.590 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)
#3: Antibody Fab Light Chain / Fragment antigen-binding


Mass: 23437.020 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: Chemical ChemComp-PVJ / 2-fluoro-4-{[(1R)-1-methyl-6-{[(2S)-oxan-2-yl]methoxy}-1-{2-oxo-2-[(1,3-thiazol-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]oxy}benzoic acid


Mass: 555.618 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30FN3O6S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 58 / 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: 2.61 Å3/Da / Density % sol: 52.82 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 0.1M Bicine pH9.0, 2% dioxane, 10% PEG 20000

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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 PILATUS3 6M / Detector: PIXEL / Date: Apr 8, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.73→151.92 Å / Num. obs: 54908 / % possible obs: 100 % / Redundancy: 10.2 % / Rmerge(I) obs: 0.073 / Net I/σ(I): 26.3
Reflection shellResolution: 2.73→2.88 Å / Rmerge(I) obs: 0.51 / Num. unique obs: 7975

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.73→38.76 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.892 / SU R Cruickshank DPI: 0.338 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.316 / SU Rfree Blow DPI: 0.234 / SU Rfree Cruickshank DPI: 0.244
RfactorNum. reflection% reflectionSelection details
Rfree0.243 2780 5.07 %RANDOM
Rwork0.227 ---
obs0.228 54844 100 %-
Displacement parametersBiso max: 113.36 Å2 / Biso mean: 57.73 Å2 / Biso min: 19.1 Å2
Baniso -1Baniso -2Baniso -3
1--0.877 Å20 Å20 Å2
2---0.877 Å20 Å2
3---1.754 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: final / Resolution: 2.73→38.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7377 0 39 58 7474
Biso mean--36.71 44.89 -
Num. residues----1000
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2436SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1292HARMONIC8
X-RAY DIFFRACTIONt_it7594HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1010SEMIHARMONIC5
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_contact8180SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7594HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg10364HARMONIC21.14
X-RAY DIFFRACTIONt_omega_torsion1.86
X-RAY DIFFRACTIONt_other_torsion12.05
LS refinement shellResolution: 2.73→2.75 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3158 62 5.65 %
Rwork0.296 1035 -
all-1097 -
obs--100 %

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