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- PDB-5vlp: PCSK9 complex with LDLR antagonist peptide and Fab7G7 -

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Basic information

Entry
Database: PDB / ID: 5vlp
TitlePCSK9 complex with LDLR antagonist peptide and Fab7G7
Components
  • Fab7G7 heavy chain
  • Fab7G7 light chain
  • LDLR antagonist peptide
  • Proprotein convertase subtilisin/kexin type 9PCSK9
KeywordsHYDROLASE / immunoglobulin / proprotein convertase / antagonist
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 / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulin subtype / Immunoglobulin / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Jelly Rolls / Alpha-Beta Plaits / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulins / Immunoglobulin-like fold / Immunoglobulin-like / Sandwich / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
MAb 6H10 light chain / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsEigenbrot, C. / Ultsch, M.
Funding support United States, 3items
OrganizationGrant numberCountry
Department of Energy (DOE, United States)DE-AC02-05CH11231 United States
Department of Energy (DOE, United States)DE-AC02-06CH11357 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P41GM103393 United States
CitationJournal: Nat. Struct. Mol. Biol. / Year: 2017
Title: Discovery of a cryptic peptide-binding site on PCSK9 and design of antagonists.
Authors: Zhang, Y. / Ultsch, M. / Skelton, N.J. / Burdick, D.J. / Beresini, M.H. / Li, W. / Kong-Beltran, M. / Peterson, A. / Quinn, J. / Chiu, C. / Wu, Y. / Shia, S. / Moran, P. / Di Lello, P. / ...Authors: Zhang, Y. / Ultsch, M. / Skelton, N.J. / Burdick, D.J. / Beresini, M.H. / Li, W. / Kong-Beltran, M. / Peterson, A. / Quinn, J. / Chiu, C. / Wu, Y. / Shia, S. / Moran, P. / Di Lello, P. / Eigenbrot, C. / Kirchhofer, D.
History
DepositionApr 25, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 18, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Dec 4, 2019Group: Author supporting evidence / Source and taxonomy / Category: pdbx_audit_support / pdbx_entity_src_syn
Item: _pdbx_audit_support.funding_organization / _pdbx_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific
Revision 1.5Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id
Revision 1.6Nov 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

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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
H: Fab7G7 heavy chain
L: Fab7G7 light chain
Z: LDLR antagonist peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,3196
Polymers125,2734
Non-polymers462
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7730 Å2
ΔGint-67 kcal/mol
Surface area43120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.865, 142.168, 239.365
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Antibody , 2 types, 2 molecules HL

#2: Antibody Fab7G7 heavy chain


Mass: 24117.857 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell (production host): hybridoma / Production host: Mus musculus (house mouse)
#3: Antibody Fab7G7 light chain


Mass: 23659.061 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: LC / Cell (production host): hybridoma / Production host: Mus musculus (house mouse) / References: UniProt: A0A0U5BC76

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Protein / Protein/peptide , 2 types, 2 molecules AZ

#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: 75566.477 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PCSK9, NARC1, PSEC0052 / Organ (production host): ovary / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#4: Protein/peptide LDLR antagonist peptide


Mass: 1929.314 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 types, 8 molecules

#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O

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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: 3.82 Å3/Da / Density % sol: 67.8 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: ammonium acetate, 1,8diaminooctane

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 29, 2017
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→70.6 Å / Num. obs: 42267 / Biso Wilson estimate: 63.48 Å2
Reflection shellResolution: 2.9→3 Å / Redundancy: 6.1 % / Mean I/σ(I) obs: 2.5 / Rsym value: 0.781 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QTW

2qtw


Resolution: 2.9→70.6 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.897 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.416 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.394 / SU Rfree Blow DPI: 0.253 / SU Rfree Cruickshank DPI: 0.26
RfactorNum. reflection% reflectionSelection details
Rfree0.209 2164 5.12 %RANDOM
Rwork0.171 ---
obs0.173 42267 99.9 %-
Displacement parametersBiso mean: 53.48 Å2
Baniso -1Baniso -2Baniso -3
1--16.4194 Å20 Å20 Å2
2--4.7849 Å20 Å2
3---11.6344 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: 1 / Resolution: 2.9→70.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7791 0 17 6 7814
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0097992HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1710862HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2667SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes163HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1183HARMONIC5
X-RAY DIFFRACTIONt_it7992HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion20.33
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1055SEMIHARMONIC5
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_contact8719SEMIHARMONIC4
LS refinement shellResolution: 2.9→2.98 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.28 167 5.44 %
Rwork0.226 2904 -
all0.229 3071 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.8775-0.21920.59972.31660.09413.58620.05820.0454-0.1171-0.31480.0250.12920.12080.2284-0.0832-0.0888-0.0486-0.0144-0.069-0.0246-0.1613-13.0359-13.3103-90.1176
21.6406-0.70560.52552.96211.0864.2249-0.06750.00720.24190.1692-0.0937-0.0617-0.0011-0.29620.16120.0146-0.0816-0.152-0.1046-0.0193-0.1988-21.7584-23.457-122.53
32.61731.70390.53626.41632.89124.3951-0.08810.1669-0.0103-0.2021-0.12810.3463-0.06060.07360.2162-0.10090.03240.0843-0.1055-0.0148-0.048-33.1944-53.4354-55.0852
40.82820.2959-0.56822.0151-0.14911.97910.0568-0.14920.07910.3632-0.11330.1913-0.0713-0.01810.0565-0.0323-0.02870.0842-0.06080.0338-0.0864-30.8477-31.6681-36.6186
53.8520.5542-1.3713.65770.65314.9567-0.01750.2849-0.2973-0.1351-0.10620.01840.1570.10870.1237-0.0925-0.05180.0333-0.07760.0432-0.0945-14.0207-23.0118-58.2793
62.6527-1.03610.35343.3923-0.0071.4995-0.0298-0.02890.00280.1502-0.0071-0.0629-0.04460.03320.037-0.0144-0.0416-0.0030.0353-0.0109-0.1217-8.6596-10.9117-68.2915
71.51510.29261.33182.6678-1.70814.88920.0207-0.0340.16280.2234-0.0185-0.3153-0.26570.32-0.00220.0344-0.10530.0254-0.0792-0.0272-0.1158-8.8545-9.2607-51.4256
81.73670.66991.5540.20540.39220.81420.0023-0.0750.08530.0541-0.0114-0.0624-0.05540.11440.00910.1867-0.06890.1030.0304-0.1129-0.1985-26.0227-17.3295-24.398
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{L|1 - L|106 H|1 - H|123}
2X-RAY DIFFRACTION2{L|107 - L|214 H|124 - H|222}
3X-RAY DIFFRACTION3{A|61 - A|145}
4X-RAY DIFFRACTION4{A|146 - A|446}
5X-RAY DIFFRACTION5{A|453 - A|530}
6X-RAY DIFFRACTION6{A|531 - A|604}
7X-RAY DIFFRACTION7{A|605 - A|682}
8X-RAY DIFFRACTION8{Z|-6 - Z|10}

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