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- PDB-6u2n: PCSK9 in complex with compound 4 -

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Basic information

Entry
Database: PDB / ID: 6u2n
TitlePCSK9 in complex with compound 4
ComponentsProprotein convertase subtilisin/kexin type 9
KeywordsHYDROLASE / Serine Type Endopeptidase Activity Proteolysis
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 / PCSK9-LDLR complex / very-low-density lipoprotein particle binding / 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 / PCSK9-LDLR complex / very-low-density lipoprotein particle binding / 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 / signaling receptor inhibitor activity / LDL clearance / positive regulation of low-density lipoprotein particle receptor catabolic process / lipoprotein metabolic process / 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 / low-density lipoprotein particle receptor binding / triglyceride metabolic process / 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 / kidney development / cholesterol homeostasis / Post-translational protein phosphorylation / neuron differentiation / cellular response to insulin stimulus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / : / positive regulation of neuron apoptotic process / late endosome / lysosome / early endosome / endoplasmic reticulum lumen / lysosomal membrane / serine-type endopeptidase activity / apoptotic process / perinuclear region of cytoplasm / Golgi apparatus / cell surface / endoplasmic reticulum / RNA binding / extracellular space / 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 / Sandwich / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-PV7 / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 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 20, 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

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Assembly

Deposited unit
A: Proprotein convertase subtilisin/kexin type 9
B: Proprotein convertase subtilisin/kexin type 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,6173
Polymers152,1632
Non-polymers4541
Water2,252125
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2720 Å2
ΔGint-16 kcal/mol
Surface area23520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.477, 70.591, 149.979
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Proprotein convertase subtilisin/kexin type 9 / 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
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: Chemical ChemComp-PV7 / 4-{[(1R)-6-methoxy-1-methyl-1-{2-oxo-2-[(1,3-thiazol-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]oxy}benzoic acid


Mass: 453.511 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23N3O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.69 Å3/Da / Density % sol: 54.25 %
Crystal growTemperature: 303 K / Method: vapor diffusion
Details: (10-22)% PEG 10000, 0.1M Tris, pH 8.5, 10% Ethylene Glycol, 1% BAM

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 21, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 30997 / % possible obs: 83.5 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.121 / Net I/σ(I): 11.1
Reflection shellResolution: 2.15→2.23 Å / Rmerge(I) obs: 0.485 / Num. unique obs: 924

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→46.78 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.899 / SU R Cruickshank DPI: 0.248 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.254 / SU Rfree Blow DPI: 0.201 / SU Rfree Cruickshank DPI: 0.201
RfactorNum. reflection% reflectionSelection details
Rfree0.234 1538 5.05 %RANDOM
Rwork0.19 ---
obs0.192 30908 83.3 %-
Displacement parametersBiso max: 146.93 Å2 / Biso mean: 47.23 Å2 / Biso min: 13.95 Å2
Baniso -1Baniso -2Baniso -3
1-4.1833 Å20 Å20 Å2
2--2.2362 Å20 Å2
3----6.4195 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.15→46.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4209 0 32 125 4366
Biso mean--32.28 47.4 -
Num. residues----571
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1425SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes746HARMONIC8
X-RAY DIFFRACTIONt_it4357HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion580SEMIHARMONIC5
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_contact4895SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4357HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5936HARMONIC21.14
X-RAY DIFFRACTIONt_omega_torsion2.3
X-RAY DIFFRACTIONt_other_torsion17.46
LS refinement shellResolution: 2.15→2.2 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2904 29 4.68 %
Rwork0.2235 590 -
all-619 -
obs--22.76 %

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