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- PDB-6xie: PCSK9(deltaCRD) in complex with cyclic peptide 77 -

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Basic information

Entry
Database: PDB / ID: 6xie
TitlePCSK9(deltaCRD) in complex with cyclic peptide 77
Components
  • (Proprotein convertase subtilisin/kexin type 9) x 2
  • Peptide 77
KeywordsHYDROLASE/INHIBITOR / protein-peptide complex / cyclic peptide / non-natural amino acids / HYDROLASE / HYDROLASE-INHIBITOR complex
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 / negative regulation of sodium ion import across 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 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 / negative regulation of sodium ion import across 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 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 / COPII-coated ER to Golgi transport vesicle / sodium channel inhibitor activity / endolysosome membrane / negative regulation of low-density lipoprotein particle clearance / signaling receptor inhibitor activity / lysosomal transport / triglyceride metabolic process / low-density lipoprotein particle receptor binding / protein autoprocessing / positive regulation of receptor internalization / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / apolipoprotein binding / cholesterol metabolic process / regulation of neuron apoptotic process / phospholipid metabolic process / neurogenesis / VLDLR internalisation and degradation / cholesterol homeostasis / cellular response to starvation / Post-translational protein phosphorylation / kidney development / liver development / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to insulin stimulus / neuron differentiation / late endosome / positive regulation of neuron apoptotic process / 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
Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.43 Å
AuthorsOrth, P.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design.
Authors: Alleyne, C. / Amin, R.P. / Bhatt, B. / Bianchi, E. / Blain, J.C. / Boyer, N. / Branca, D. / Embrey, M.W. / Ha, S.N. / Jette, K. / Johns, D.G. / Kerekes, A.D. / Koeplinger, K.A. / LaPlaca, D. ...Authors: Alleyne, C. / Amin, R.P. / Bhatt, B. / Bianchi, E. / Blain, J.C. / Boyer, N. / Branca, D. / Embrey, M.W. / Ha, S.N. / Jette, K. / Johns, D.G. / Kerekes, A.D. / Koeplinger, K.A. / LaPlaca, D. / Li, N. / Murphy, B. / Orth, P. / Ricardo, A. / Salowe, S. / Seyb, K. / Shahripour, A. / Stringer, J.R. / Sun, Y. / Tracy, R. / Wu, C. / Xiong, Y. / Youm, H. / Zokian, H.J. / Tucker, T.J.
History
DepositionJun 19, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 2, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
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: Advisory / Atomic model ...Advisory / 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_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_main_chain_plane / pdbx_validate_peptide_omega / pdbx_validate_rmsd_angle / struct_conn / struct_ref_seq / struct_sheet_range / struct_site / struct_site_gen
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_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_nonpoly_scheme.auth_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 / _struct_site.pdbx_auth_seq_id / _struct_site.pdbx_num_residues

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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
I: Peptide 77
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0314
Polymers47,9393
Non-polymers921
Water6,197344
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3790 Å2
ΔGint-23 kcal/mol
Surface area15590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.875, 70.875, 166.304
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Components on special symmetry positions
IDModelComponents
11B-720-

HOH

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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: 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
#3: Protein/peptide Peptide 77


Mass: 1310.556 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 344 / 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: 2.56 Å3/Da / Density % sol: 51.87 %
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: Jun 30, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.43→61.38 Å / Num. obs: 80563 / % possible obs: 94.8 % / Redundancy: 9.8 % / CC1/2: 0.999 / Net I/σ(I): 17.8
Reflection shellResolution: 1.432→1.505 Å / Num. unique obs: 4027 / CC1/2: 0.697

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (6-FEB-2020)refinement
XDSdata reduction
STARANISOdata scaling
MOLREPphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4nmx

4nmx


Resolution: 1.43→61.38 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.953 / SU R Cruickshank DPI: 0.064 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.067 / SU Rfree Blow DPI: 0.068 / SU Rfree Cruickshank DPI: 0.065
RfactorNum. reflection% reflectionSelection details
Rfree0.2214 4026 5 %RANDOM
Rwork0.1993 ---
obs0.2004 80552 89.3 %-
Displacement parametersBiso max: 83.8 Å2 / Biso mean: 28.27 Å2 / Biso min: 16.84 Å2
Baniso -1Baniso -2Baniso -3
1-0.0475 Å20 Å20 Å2
2--0.0475 Å20 Å2
3----0.0951 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.43→61.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2857 0 6 344 3207
Biso mean--30.41 40.35 -
Num. residues----380
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d980SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes500HARMONIC5
X-RAY DIFFRACTIONt_it2926HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion382SEMIHARMONIC5
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_contact2937SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2927HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3980HARMONIC20.94
X-RAY DIFFRACTIONt_omega_torsion3.54
X-RAY DIFFRACTIONt_other_torsion13.87
LS refinement shellResolution: 1.43→1.48 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.228 76 4.71 %
Rwork0.2278 1536 -
all0.2278 1612 -
obs--19.37 %

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