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- PDB-7s5g: PCSK9 in complex with compound 19 -

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Basic information

Entry
Database: PDB / ID: 7s5g
TitlePCSK9 in complex with compound 19
Components
  • Propeptide of Proprotein convertase subtilisin/kexin type 9
  • Proprotein convertase subtilisin/kexin type 9
  • Z9J-ALA-DAL-PHE-FTR-PRO-THR-0A1-3WX
KeywordsPROTEIN BINDING / HYDROLASE / cholesterol / LDL receptor / EGFA domain
Function / homology
Function and homology information


low-density lipoprotein particle receptor catabolic process / : / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / extrinsic component of external side of plasma membrane / PCSK9-LDLR complex / PCSK9-AnxA2 complex / : / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding ...low-density lipoprotein particle receptor catabolic process / : / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / extrinsic component of external side of plasma membrane / PCSK9-LDLR complex / PCSK9-AnxA2 complex / : / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding / negative regulation of low-density lipoprotein particle clearance / low-density lipoprotein particle binding / positive regulation of low-density lipoprotein particle receptor catabolic process / LDL clearance / lipoprotein metabolic process / very-low-density lipoprotein particle receptor binding / negative regulation of receptor internalization / : / regulation of signaling receptor activity / endolysosome membrane / sodium channel inhibitor activity / signaling receptor inhibitor activity / lysosomal transport / triglyceride metabolic process / low-density lipoprotein particle receptor binding / COPII-coated ER to Golgi transport vesicle / protein autoprocessing / positive regulation of receptor internalization / apolipoprotein binding / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / regulation of neuron apoptotic process / phospholipid metabolic process / neurogenesis / cholesterol metabolic process / VLDLR internalisation and degradation / cholesterol homeostasis / liver development / cellular response to starvation / kidney development / Post-translational protein phosphorylation / cellular response to insulin stimulus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron differentiation / positive regulation of neuron apoptotic process / late endosome / early endosome / lysosome / endoplasmic reticulum lumen / lysosomal membrane / serine-type endopeptidase activity / apoptotic process / perinuclear region of cytoplasm / cell surface / endoplasmic reticulum / Golgi apparatus / 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 / Peptidase S8/S53 domain / : / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
(2E)-but-2-ene-1,4-diol / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.041 Å
AuthorsOrth, P.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2021
Title: A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.
Authors: Tucker, T.J. / Embrey, M.W. / Alleyne, C. / Amin, R.P. / Bass, A. / Bhatt, B. / Bianchi, E. / Branca, D. / Bueters, T. / Buist, N. / Ha, S.N. / Hafey, M. / He, H. / Higgins, J. / Johns, D.G. ...Authors: Tucker, T.J. / Embrey, M.W. / Alleyne, C. / Amin, R.P. / Bass, A. / Bhatt, B. / Bianchi, E. / Branca, D. / Bueters, T. / Buist, N. / Ha, S.N. / Hafey, M. / He, H. / Higgins, J. / Johns, D.G. / Kerekes, A.D. / Koeplinger, K.A. / Kuethe, J.T. / Li, N. / Murphy, B. / Orth, P. / Salowe, S. / Shahripour, A. / Tracy, R. / Wang, W. / Wu, C. / Xiong, Y. / Zokian, H.J. / Wood, H.B. / Walji, A.
History
DepositionSep 10, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 3, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 15, 2023Group: Data collection / Derived calculations / Category: chem_comp_atom / chem_comp_bond / struct_conn
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag
Revision 2.0Apr 24, 2024Group: Atomic model / Author supporting evidence ...Atomic model / Author supporting evidence / Data collection / Database references / Derived calculations / Non-polymer description / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_instance_feature / pdbx_entity_src_syn / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_validate_main_chain_plane / pdbx_validate_peptide_omega / pdbx_validate_rmsd_angle / struct_conn / struct_ref_seq / struct_sheet_range
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.group_PDB / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_seq_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_ec / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.gene_src_common_name / _entity_src_gen.host_org_common_name / _entity_src_gen.pdbx_host_org_vector_type / _pdbx_entity_instance_feature.auth_comp_id / _pdbx_entity_instance_feature.comp_id / _pdbx_entity_src_syn.pdbx_end_seq_num / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_auth_seq_id / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_auth_seq_id / _struct_sheet_range.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Propeptide of Proprotein convertase subtilisin/kexin type 9
B: Proprotein convertase subtilisin/kexin type 9
C: Z9J-ALA-DAL-PHE-FTR-PRO-THR-0A1-3WX
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0745
Polymers47,8943
Non-polymers1802
Water2,270126
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4170 Å2
ΔGint-29 kcal/mol
Surface area16280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.027, 71.027, 153.606
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Propeptide of Proprotein convertase subtilisin/kexin type 9


Mass: 13791.463 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: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: 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: 32836.910 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: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases

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Protein/peptide , 1 types, 1 molecules C

#3: Protein/peptide Z9J-ALA-DAL-PHE-FTR-PRO-THR-0A1-3WX


Mass: 1265.515 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 3 types, 128 molecules

#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-89N / (2E)-but-2-ene-1,4-diol


Mass: 88.105 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H8O2
Details: cross-linker of phenylalanine and proline side chains in the cyclic peptide
Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.34 Å3/Da / Density % sol: 47.35 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 20% PEG3350, 200mM CaCl2, 100mM MES pH 6

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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 PILATUS 6M / Detector: PIXEL / Date: Mar 30, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.041→61.51 Å / Num. obs: 21355 / % possible obs: 84.7 % / Redundancy: 9.6 % / CC1/2: 0.993 / Net I/σ(I): 7.2
Reflection shellResolution: 2.041→2.181 Å / Num. unique obs: 1069 / CC1/2: 0.51

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (11-DEC-2020)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
STARANISOdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2W2M

2w2m


Resolution: 2.041→61.51 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.877 / SU R Cruickshank DPI: 0.299 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.31 / SU Rfree Blow DPI: 0.246 / SU Rfree Cruickshank DPI: 0.245
RfactorNum. reflection% reflectionSelection details
Rfree0.2856 450 2.11 %RANDOM
Rwork0.2274 ---
obs0.2286 21355 72.8 %-
Displacement parametersBiso max: 63.74 Å2 / Biso mean: 26.68 Å2 / Biso min: 10.79 Å2
Baniso -1Baniso -2Baniso -3
1-0.5592 Å20 Å20 Å2
2--0.5592 Å20 Å2
3----1.1185 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.041→61.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2925 0 15 126 3066
Biso mean--28.37 28.59 -
Num. residues----389
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d999SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes511HARMONIC5
X-RAY DIFFRACTIONt_it3005HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion393SEMIHARMONIC5
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_contact2475SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3006HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg4088HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion16.71
LS refinement shellResolution: 2.041→2.17 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3362 26 2.68 %
Rwork0.2899 945 -
obs--19.82 %

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