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- PDB-6u26: PCSK9 in complex with compound 16 -

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Basic information

Entry
Database: PDB / ID: 6u26
TitlePCSK9 in complex with compound 16
ComponentsProprotein convertase subtilisin/kexin type 9PCSK9
KeywordsHYDROLASE/HYDROLASE Inhibitor / CHOLESTEROL CLEARANCE / PCSK9 / LDLR / Autocatalytic cleavage / Cholesterol metabolism / Disulfide bond / Glycoprotein / Hydrolase / Lipid metabolism / Phosphoprotein / Protease / Secreted / Serine protease / inhibitor / HYDROLASE-HYDROLASE Inhibitor 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 / Sandwich / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-063 / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 Å
AuthorsOrth, P.
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 19, 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
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)153,2413
Polymers152,1632
Non-polymers1,0771
Water5,765320
1
A: Proprotein convertase subtilisin/kexin type 9


Theoretical massNumber of molelcules
Total (without water)76,0821
Polymers76,0821
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Proprotein convertase subtilisin/kexin type 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,1592
Polymers76,0821
Non-polymers1,0771
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)62.680, 70.920, 150.120
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 / 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 / Production host: Homo sapiens (human)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Chemical ChemComp-063 / 4'-{[(1R)-6-{2-[2-({N~5~-[N,N'-bis(tert-butoxycarbonyl)carbamimidoyl]-N~2~-(tert-butoxycarbonyl)-L-ornithyl}amino)ethoxy]ethoxy}-1-methyl-1-{2-oxo-2-[(1,3-thiazol-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]oxy}-2'-fluoro[1,1'-biphenyl]-4-carboxylic acid


Mass: 1077.224 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C53H69FN8O13S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 320 / 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: 1.1 Å3/Da / Density % sol: 54.68 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 100 mM Tris (pH 7.8) 200 mM NaCl, 15% PEG 3350,

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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: Jun 12, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.53→150 Å / Num. obs: 75722 / % possible obs: 100 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.081 / Net I/σ(I): 13.1
Reflection shellResolution: 1.53→1.66 Å / Rmerge(I) obs: 1.11 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 3787

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
autoPROCdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.53→22.12 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.945 / SU R Cruickshank DPI: 0.09 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.092 / SU Rfree Blow DPI: 0.09 / SU Rfree Cruickshank DPI: 0.089
RfactorNum. reflection% reflectionSelection details
Rfree0.213 3848 5.08 %RANDOM
Rwork0.187 ---
obs0.189 75681 74.5 %-
Displacement parametersBiso max: 121.46 Å2 / Biso mean: 28.77 Å2 / Biso min: 11.01 Å2
Baniso -1Baniso -2Baniso -3
1-0.0618 Å20 Å20 Å2
2---0.2099 Å20 Å2
3---0.1481 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.53→22.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4238 0 76 320 4634
Biso mean--41.95 33.54 -
Num. residues----571
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1468SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes758HARMONIC5
X-RAY DIFFRACTIONt_it4410HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion578SEMIHARMONIC5
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_contact5325SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4410HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6007HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion3.63
X-RAY DIFFRACTIONt_other_torsion15.33
LS refinement shellResolution: 1.53→1.61 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2461 67 4.43 %
Rwork0.2131 1447 -
all0.2145 1514 -
obs--10.23 %

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