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- PDB-6xib: PCSK9(deltaCRD) in complex with cyclic peptide 30 -

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Basic information

Entry
Database: PDB / ID: 6xib
TitlePCSK9(deltaCRD) in complex with cyclic peptide 30
Components
  • (Proprotein convertase subtilisin/kexin type 9) x 2
  • Peptide 30
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 / positive regulation of low-density lipoprotein particle receptor catabolic process ...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 / positive regulation of low-density lipoprotein particle receptor catabolic process / low-density lipoprotein particle binding / 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 / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / positive regulation of receptor internalization / 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: 1.546 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 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_name_com / 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 / 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.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_gene_src_gene / _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.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific / _pdbx_entity_src_syn.pdbx_end_seq_num / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_unobs_or_zero_occ_atoms.auth_comp_id / _pdbx_unobs_or_zero_occ_atoms.label_comp_id / _pdbx_unobs_or_zero_occ_atoms.label_seq_id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq.db_align_beg / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id / _struct_site.pdbx_num_residues

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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
I: Peptide 30
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,2424
Polymers48,1503
Non-polymers921
Water6,143341
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3970 Å2
ΔGint-24 kcal/mol
Surface area16230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.027, 71.027, 152.357
Angle α, β, γ (deg.)90, 90, 120
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein 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 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8NBP7
#2: Protein Proprotein convertase subtilisin/kexin type 9


Mass: 32836.910 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PCSK9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8NBP7
#3: Protein/peptide Peptide 30


Mass: 1521.711 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 341 / 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: 2.59 Å3/Da / Density % sol: 52.56 %
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 PILATUS3 S 6M / Detector: PIXEL / Date: Dec 5, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.546→61.511 Å / Num. obs: 57785 / % possible obs: 92.7 % / Redundancy: 9.3 % / CC1/2: 0.998 / Net I/σ(I): 8.6
Reflection shellResolution: 1.546→1.631 Å / Num. unique obs: 2883 / CC1/2: 0.577

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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: 1.546→61.51 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.95 / SU R Cruickshank DPI: 0.083 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.088 / SU Rfree Blow DPI: 0.082 / SU Rfree Cruickshank DPI: 0.079
RfactorNum. reflection% reflectionSelection details
Rfree0.2047 1111 -RANDOM
Rwork0.1891 ---
obs0.1894 57717 87.5 %-
Displacement parametersBiso mean: 24.28 Å2
Baniso -1Baniso -2Baniso -3
1-0.1529 Å20 Å20 Å2
2--0.1529 Å20 Å2
3----0.3058 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: LAST / Resolution: 1.546→61.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2951 0 6 341 3298
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0083022HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.94111HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1009SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes517HARMONIC5
X-RAY DIFFRACTIONt_it3022HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion391SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2802SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.35
X-RAY DIFFRACTIONt_other_torsion14.9
LS refinement shellResolution: 1.55→1.59 Å
RfactorNum. reflection% reflection
Rfree0.244 17 -
Rwork0.2038 --
obs0.2044 1155 20.18 %

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