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- PDB-4k8r: An Antibody Against the C-terminal Domain of PCSK9 lowers LDL Cho... -

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Basic information

Entry
Database: PDB / ID: 4k8r
TitleAn Antibody Against the C-terminal Domain of PCSK9 lowers LDL Cholesterol Levels in vivo
Components
  • (Proprotein convertase subtilisin/kexin type ...) x 2
  • Fab1, heavy chain
  • Fab1, light chain
  • Fab3H42, heavy chain
  • Fab3H42, light chain
KeywordsIMMUNE SYSTEM / Immunoglobulin
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 / PCSK9-LDLR complex / very-low-density lipoprotein particle binding / 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 / PCSK9-LDLR complex / very-low-density lipoprotein particle binding / 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 / signaling receptor inhibitor activity / LDL clearance / positive regulation of low-density lipoprotein particle receptor catabolic process / lipoprotein metabolic process / 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 / low-density lipoprotein particle receptor binding / triglyceride metabolic process / 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 / kidney development / cholesterol homeostasis / Post-translational protein phosphorylation / neuron differentiation / cellular response to insulin stimulus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / : / positive regulation of neuron apoptotic process / late endosome / lysosome / early endosome / endoplasmic reticulum lumen / lysosomal membrane / serine-type endopeptidase activity / apoptotic process / perinuclear region of cytoplasm / Golgi apparatus / cell surface / endoplasmic reticulum / RNA binding / extracellular space / 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 / Jelly Rolls / Alpha-Beta Plaits / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.22 Å
AuthorsSchiele, F. / Nar, H.
CitationJournal: J.Mol.Biol. / Year: 2014
Title: An Antibody against the C-Terminal Domain of PCSK9 Lowers LDL Cholesterol Levels In Vivo.
Authors: Schiele, F. / Park, J. / Redemann, N. / Luippold, G. / Nar, H.
History
DepositionApr 18, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2013Group: Database references
Revision 1.2Feb 19, 2014Group: Database references
Revision 1.3Aug 21, 2019Group: Advisory / Data collection / Structure summary / Category: entity / pdbx_unobs_or_zero_occ_atoms / Item: _entity.pdbx_description

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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
C: Fab1, light chain
D: Fab1, heavy chain
H: Fab3H42, heavy chain
L: Fab3H42, light chain


Theoretical massNumber of molelcules
Total (without water)165,2476
Polymers165,2476
Non-polymers00
Water5,080282
1
A: Proprotein convertase subtilisin/kexin type 9
B: Proprotein convertase subtilisin/kexin type 9


Theoretical massNumber of molelcules
Total (without water)69,0052
Polymers69,0052
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2550 Å2
ΔGint-16 kcal/mol
Surface area24400 Å2
MethodPISA
2
C: Fab1, light chain
D: Fab1, heavy chain


Theoretical massNumber of molelcules
Total (without water)48,1262
Polymers48,1262
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3630 Å2
ΔGint-25 kcal/mol
Surface area19850 Å2
MethodPISA
3
H: Fab3H42, heavy chain
L: Fab3H42, light chain


Theoretical massNumber of molelcules
Total (without water)48,1162
Polymers48,1162
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3120 Å2
ΔGint-22 kcal/mol
Surface area19380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)262.190, 138.650, 69.540
Angle α, β, γ (deg.)90.00, 102.87, 90.00
Int Tables number5
Space group name H-MC121
DetailsFab1 consists of chain C and D / Fab3H42 consists of chain L and H / PCSK9 consists of chain A and B

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Components

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Proprotein convertase subtilisin/kexin type ... , 2 types, 2 molecules AB

#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: 10490.109 Da / Num. of mol.: 1 / Fragment: unp residues 61-152
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NARC1, PCSK9, PSEC0052 / Production host: Escherichia coli (E. coli)
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: 58514.898 Da / Num. of mol.: 1 / Fragment: unp residues 153-692 / Mutation: V474I, G670E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NARC1, PCSK9, PSEC0052 / Production host: Escherichia coli (E. coli)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases

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Antibody , 4 types, 4 molecules CDHL

#3: Antibody Fab1, light chain


Mass: 23248.785 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 Fab1, heavy chain


Mass: 24877.518 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)
#5: Antibody Fab3H42, heavy chain


Mass: 25489.293 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)
#6: Antibody Fab3H42, light chain


Mass: 22626.869 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)

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Non-polymers , 1 types, 282 molecules

#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 282 / 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: 3.73 Å3/Da / Density % sol: 67.01 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.5 M lithium sulfate, 0.1 M disodium malonate, 11.5 % PEG 8K , pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 3.22→127.8 Å / Num. obs: 38982 / Biso Wilson estimate: 60.08 Å2

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Processing

SoftwareName: BUSTER / Version: 2.11.2 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.22→40 Å / Cor.coef. Fo:Fc: 0.8955 / Cor.coef. Fo:Fc free: 0.8471 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2264 1956 5.02 %RANDOM
Rwork0.1674 ---
obs0.1704 38968 99.14 %-
Displacement parametersBiso mean: 80.31 Å2
Baniso -1Baniso -2Baniso -3
1--8.1408 Å20 Å2-15.2087 Å2
2--1.5575 Å20 Å2
3---6.5833 Å2
Refine analyzeLuzzati coordinate error obs: 0.52 Å
Refinement stepCycle: LAST / Resolution: 3.22→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10963 0 0 282 11245
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00811220HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0815267HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3703SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes225HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1666HARMONIC5
X-RAY DIFFRACTIONt_it11220HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.33
X-RAY DIFFRACTIONt_other_torsion21.44
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1481SEMIHARMONIC5
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_contact12652SEMIHARMONIC4
LS refinement shellResolution: 3.22→3.3 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2914 140 4.93 %
Rwork0.2098 2702 -
all0.2138 2842 -
obs--99.14 %
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)
11.6705-0.0314-0.013.8991.17352.2074-0.1136-0.25160.12980.28610.2369-0.5215-0.1930.5658-0.1233-0.0582-0.03980.01350.045-0.0284-0.154457.6394-46.95750.8005
21.4001-1.35680.05732.6917-0.03870.96570.0642-0.0911-0.1066-0.0967-0.0752-0.19240.26230.13420.0111-0.00610.01140.049-0.1590.0357-0.268556.2398-74.4773-14.529
312.24432.8112-3.45680.00170.6439-0.5745-0.14080.61510.4788-0.12950.1969-0.4614-0.28480.5768-0.0561-0.0862-0.22440.4673-0.3351-0.11390.0752100.0097-51.2528-27.3979
41.52131.21541.81151.95790.3550.7483-0.15060.08740.17050.0350.2187-0.35120.1721-0.0437-0.0681-0.2501-0.00890.361-0.1901-0.1530.3331117.6693-24.2479-9.9451
55.43083.48633.81585.95792.29662.90450.0394-0.93390.53780.23180.1248-0.7697-0.20310.4742-0.1642-0.4351-0.05890.3481-0.0527-0.24920.203588.0119-52.7209-10.4401
63.81052.07210.29150.05892.3235-0.0657-0.00580.03190.0926-0.05-0.00190.1322-0.25130.07040.0078-0.2061-0.02380.2788-0.2938-0.11280.248102.4252-22.9514-6.3121
70.36230.04991.05850.2189-0.42352.8777-0.0858-0.0547-0.04520.08140.02040.0490.0012-0.29350.0654-0.07140.02690.01560.098-0.0255-0.129930.0685-46.059-50.6617
81.1317-0.14390.4720.5718-0.55222.0775-0.07430.06570.16190.0059-0.07630.0135-0.00340.14150.1506-0.0767-0.0105-0.03320.0083-0.051-0.161845.0392-39.1566-58.4081
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|61 - A|152 }A61 - 152
2X-RAY DIFFRACTION2{ B|153 - B|682 }B153 - 682
3X-RAY DIFFRACTION3{ C|2 - C|109 }C2 - 109
4X-RAY DIFFRACTION4{ C|110 - C|214 }C110 - 214
5X-RAY DIFFRACTION5{ D|1 - D|132 }D1 - 132
6X-RAY DIFFRACTION6{ D|133 - D|229 }D133 - 229
7X-RAY DIFFRACTION7{ H|1 - H|224 }H1 - 224
8X-RAY DIFFRACTION8{ L|1 - L|214 }L1 - 214

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