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- PDB-5vl7: PCSK9 complex with Fab33 -

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Basic information

Entry
Database: PDB / ID: 5vl7
TitlePCSK9 complex with Fab33
Components
  • (Proprotein convertase subtilisin/kexin type 9PCSK9) x 2
  • Fab33 heavy chain
  • Fab33 light chain
KeywordsHYDROLASE / immunoglobulin proprotein convertase / subtilisin
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
Ig-like domain-containing protein / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsEigenbrot, C. / Shia, S.
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 / Database references / Category: pdbx_audit_support / struct_ref_seq
Item: _pdbx_audit_support.funding_organization / _struct_ref_seq.db_align_end
Revision 1.5Oct 4, 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

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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
H: Fab33 heavy chain
L: Fab33 light chain


Theoretical massNumber of molelcules
Total (without water)123,0174
Polymers123,0174
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8190 Å2
ΔGint-46 kcal/mol
Surface area39660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.283, 142.523, 253.983
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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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: 17035.453 Da / Num. of mol.: 1 / Fragment: prodomain residues 1-152
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
#2: 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: 58548.922 Da / Num. of mol.: 1
Fragment: catalytic and cysteine-rich domains, residues 153-692
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
#3: Antibody Fab33 heavy chain


Mass: 24138.037 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Antibody Fab33 light chain


Mass: 23294.854 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: Q7Z3Y4

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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: 3.39 Å3/Da / Density % sol: 63.76 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: potassium sodium phosphate

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 13, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 3.5→40 Å / Num. obs: 21579 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7.3 % / Biso Wilson estimate: 60.9 Å2 / Rsym value: 0.184 / Net I/σ(I): 11
Reflection shellResolution: 3.5→3.63 Å / Redundancy: 7.4 % / Mean I/σ(I) obs: 2.6 / Num. unique obs: 2114 / Rsym value: 0.807 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QTW

2qtw


Resolution: 3.5→37.75 Å / Cor.coef. Fo:Fc: 0.888 / Cor.coef. Fo:Fc free: 0.845 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.483
RfactorNum. reflection% reflectionSelection details
Rfree0.245 903 4.19 %RANDOM
Rwork0.199 ---
obs0.201 21547 99.9 %-
Displacement parametersBiso mean: 105.68 Å2
Baniso -1Baniso -2Baniso -3
1--30.3056 Å20 Å20 Å2
2--15.3919 Å20 Å2
3---14.9137 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: 1 / Resolution: 3.5→37.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7195 0 0 0 7195
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0087352HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.139996HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2445SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes153HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1084HARMONIC5
X-RAY DIFFRACTIONt_it7352HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.49
X-RAY DIFFRACTIONt_other_torsion21.24
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion979SEMIHARMONIC5
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_contact8221SEMIHARMONIC4
LS refinement shellResolution: 3.5→3.67 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.266 119 4.23 %
Rwork0.216 2697 -
all0.218 2816 -
obs--99.4 %
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)
10.98190.7691.42845.34172.91040.3004-0.07010.0984-0.1621-0.1984-0.40410.06020.03820.13850.4742-0.15860.06040.1460.165-0.152-0.0121-27.9201-14.025569.6667
20.50970.0094-0.20971.4160.30130.63970.01730.20080.00070.1966-0.2563-0.0459-0.0181-0.0360.239-0.11950.03960.04820.13090.07210.0461-25.26357.531587.3435
300.0209-1.57481.311-2.91041.756-0.2049-0.09590.1753-0.2871-0.1345-0.20810.3551-0.12720.3394-0.04020.03310.1520.07540.1520.0613-9.243224.91564.3725
40.077-0.049-0.66160.69550.17062.25470.07610.03660.04470.2575-0.0421-0.1059-0.19590.1316-0.0340.304-0.13260.0612-0.1190.0093-0.1045-27.690419.136120.105
500.9827-0.94563.73562.692.35040.1792-0.39130.26330.06610.18580.41650.12490.474-0.3650.304-0.1520.1284-0.2551-0.152-0.1102-32.214642.9619145.286
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|61 - A|152}
2X-RAY DIFFRACTION2{B|179 - B|447}
3X-RAY DIFFRACTION3{B|454 - B|681}
4X-RAY DIFFRACTION4{L|2 - L|108 H|1 - H|121}
5X-RAY DIFFRACTION5{L|109 - L|211 H|122 - H|216}

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