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- PDB-3m0c: The X-ray Crystal Structure of PCSK9 in Complex with the LDL receptor -

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Basic information

Entry
Database: PDB / ID: 3m0c
TitleThe X-ray Crystal Structure of PCSK9 in Complex with the LDL receptor
Components
  • (Proprotein convertase subtilisin/kexin type 9) x 2
  • Low-density lipoprotein receptor
KeywordsPROTEIN BINDING / PROTEIN COMPLEX / BETA PROPELLER / CHOLESTEROL CLEARANCE / PCSK9 / LDLR / Autocatalytic cleavage / Cholesterol metabolism / Disease mutation / Disulfide bond / Glycoprotein / Hydrolase / Lipid metabolism / Phosphoprotein / Protease / Secreted / Serine protease / Steroid metabolism / Zymogen / Coated pit / EGF-like domain / Endocytosis / Host-virus interaction / LDL / Lipid transport / Membrane / Receptor / Transmembrane / Transport
Function / homology
Function and homology information


receptor-mediated endocytosis involved in cholesterol transport / regulation of phosphatidylcholine catabolic process / plasma lipoprotein particle clearance / positive regulation of lysosomal protein catabolic process / negative regulation of astrocyte activation / 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 microglial cell activation / negative regulation of sodium ion import across plasma membrane ...receptor-mediated endocytosis involved in cholesterol transport / regulation of phosphatidylcholine catabolic process / plasma lipoprotein particle clearance / positive regulation of lysosomal protein catabolic process / negative regulation of astrocyte activation / 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 microglial cell activation / negative regulation of sodium ion import across plasma membrane / very-low-density lipoprotein particle receptor activity / PCSK9-LDLR complex / cholesterol import / PCSK9-AnxA2 complex / low-density lipoprotein particle clearance / positive regulation of triglyceride biosynthetic process / clathrin heavy chain binding / negative regulation of receptor recycling / apolipoprotein receptor binding / intestinal cholesterol absorption / very-low-density lipoprotein particle binding / low-density lipoprotein particle receptor activity / Chylomicron clearance / amyloid-beta clearance by cellular catabolic process / low-density lipoprotein particle binding / positive regulation of low-density lipoprotein particle receptor catabolic process / response to caloric restriction / LDL clearance / lipoprotein metabolic process / high-density lipoprotein particle clearance / regulation of protein metabolic process / very-low-density lipoprotein particle receptor binding / lipoprotein catabolic process / phospholipid transport / low-density lipoprotein particle / cholesterol transport / negative regulation of receptor internalization / COPII-coated ER to Golgi transport vesicle / endolysosome membrane / sodium channel inhibitor activity / cellular response to fatty acid / negative regulation of amyloid fibril formation / negative regulation of low-density lipoprotein particle clearance / signaling receptor inhibitor activity / regulation of cholesterol metabolic process / artery morphogenesis / negative regulation of protein metabolic process / lysosomal transport / triglyceride metabolic process / low-density lipoprotein particle receptor binding / sorting endosome / amyloid-beta clearance / lipoprotein particle binding / protein autoprocessing / positive regulation of receptor internalization / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / apolipoprotein binding / cellular response to low-density lipoprotein particle stimulus / long-term memory / phagocytosis / retinoid metabolic process / cholesterol metabolic process / Retinoid metabolism and transport / regulation of neuron apoptotic process / phospholipid metabolic process / clathrin-coated pit / neurogenesis / somatodendritic compartment / receptor-mediated endocytosis / VLDLR internalisation and degradation / cholesterol homeostasis / cellular response to starvation / Post-translational protein phosphorylation / kidney development / clathrin-coated endocytic vesicle membrane / liver development / lipid metabolic process / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / endocytosis / cellular response to insulin stimulus / neuron differentiation / positive regulation of inflammatory response / apical part of cell / late endosome / Cargo recognition for clathrin-mediated endocytosis / positive regulation of neuron apoptotic process / Clathrin-mediated endocytosis / amyloid-beta binding / virus receptor activity / protease binding / basolateral plasma membrane / molecular adaptor activity / early endosome / lysosome / receptor complex / endosome membrane / endoplasmic reticulum lumen / negative regulation of gene expression / lysosomal membrane / external side of plasma membrane
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 / Complement Clr-like EGF-like / : / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. ...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 / Complement Clr-like EGF-like / : / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Low-density lipoprotein receptor domain class A / : / Calcium-binding EGF domain / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Proteinase K-like catalytic domain / Peptidase S8 propeptide/proteinase inhibitor I9 / Peptidase inhibitor I9 / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Six-bladed beta-propeller, TolB-like / Peptidase S8 propeptide/proteinase inhibitor I9 superfamily / : / Coagulation Factor Xa inhibitory site / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 2. / EGF-like domain
Similarity search - Domain/homology
Low-density lipoprotein receptor / Proprotein convertase subtilisin/kexin type 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 7.01 Å
AuthorsSpraggon, G. / Hampton, E.N.
CitationJournal: To be Published
Title: The X-ray Crystal Structure of PCSK9 in Complex with the LDL receptor
Authors: Li, J. / Gavigan, J.A. / Zheng, G. / Huang, W. / Yowe, D. / Geisse, S. / Harris, J.L. / Lesley, S.A. / Spraggon, G.
History
DepositionMar 2, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 27, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
C: Low-density lipoprotein receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,1556
Polymers160,0343
Non-polymers1203
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)322.906, 322.906, 76.733
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#1: Protein Proprotein convertase subtilisin/kexin type 9 / Proprotein convertase 9 / PC9 / Subtilisin/kexin-like protease PC9 / Neural apoptosis-regulated ...Proprotein convertase 9 / PC9 / Subtilisin/kexin-like protease PC9 / Neural apoptosis-regulated convertase 1 / NARC-1


Mass: 14019.734 Da / Num. of mol.: 1 / Fragment: PCSK9
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NARC1, PCSK9, PSEC0052 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Protein Proprotein convertase subtilisin/kexin type 9 / Proprotein convertase 9 / PC9 / Subtilisin/kexin-like protease PC9 / Neural apoptosis-regulated ...Proprotein convertase 9 / PC9 / Subtilisin/kexin-like protease PC9 / Neural apoptosis-regulated convertase 1 / NARC-1


Mass: 58320.707 Da / Num. of mol.: 1 / Fragment: PCSK9 / Mutation: D374Y
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NARC1, PCSK9, PSEC0052 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: Q8NBP7, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#3: Protein Low-density lipoprotein receptor / LDL receptor


Mass: 87693.984 Da / Num. of mol.: 1 / Fragment: LDLR
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LDLR / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P01130
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
Has protein modificationY

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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

Crystal growTemperature: 297 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 1.4 M Ammonium phosphate, 0.2M sodium chloride in 0.1M Imidazole buffer, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9775 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 28, 2009 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9775 Å / Relative weight: 1
ReflectionResolution: 7.01→279.645 Å / Num. all: 6162 / Num. obs: 6162 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.8 % / Rmerge(I) obs: 0.173 / Rsym value: 0.173 / Net I/σ(I): 3.2
Reflection shellResolution: 7.01→7.38 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.776 / Mean I/σ(I) obs: 0.6 / Rsym value: 0.776 / % possible all: 98.2

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Processing

Software
NameVersionClassification
PHASERphasing
PHENIX(phenix.refine)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 2QTW, 1IJQ

2qtw

1ijq


Resolution: 7.01→279.64 Å / SU ML: 4.32 / Isotropic thermal model: Overall / σ(F): 0 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.362 290 4.71 %
Rwork0.341 --
obs0.342 6162 82.2 %
all-6162 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 150 Å2 / ksol: 0.37 e/Å3
Displacement parametersBiso mean: 182.3 Å2
Refinement stepCycle: LAST / Resolution: 7.01→279.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7687 0 3 0 7690
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0197882
X-RAY DIFFRACTIONf_angle_d2.28610672
X-RAY DIFFRACTIONf_dihedral_angle_d18.8712831
X-RAY DIFFRACTIONf_chiral_restr0.1141210
X-RAY DIFFRACTIONf_plane_restr0.011396
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
7.01-8.8330.46241170.43632462X-RAY DIFFRACTION70
8.833-279.86770.33121730.30373410X-RAY DIFFRACTION94
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)
13.06280.74862.37161.0177-2.31981.4064-0.58311.1247-0.1768-0.2337-0.49080.25042.7757-1.17250.93741.6859-0.9557-0.05831.3633-0.07741.2087110.2597-121.9496-11.6892
27.7106-3.19663.93217.3903-5.34191.82340.31721.0338-0.5432.0134-0.10851.2071-1.00760.0639-0.26330.91990.35250.28410.0828-0.43761.1669119.6647-88.823-5.2715
3-0.73833.1055-1.87466.1691-2.12525.57970.57580.8807-1.130.4983-0.3753-0.0518-0.613-2.0143-0.9370.45310.22470.75082.0053-0.5671.9595122.2714-78.50276.6111
47.1262-4.75050.866.3338-1.12521.4971-2.3690.1623-1.52073.8255-0.31221.3081-0.5665-0.58911.47281.52460.3974-0.0922-0.2771-1.01121.5043127.9806-75.4454-8.8299
52.9263-2.4662-1.39954.3843.10144.9317-0.2212-0.1010.63810.74910.19860.29460.57510.58420.22521.2703-0.77010.00111.85030.23461.9947131.5864-105.3878-24.9053
6-3.0144-1.95532.92381.3553-0.3205-0.04530.18660.49910.96940.0473-1.9205-0.20980.64030.82170.6440.72220.11181.79482.29610.4711.8938159.6315-115.589-54.4792
71.0477-5.2112-0.69975.0242-5.16939.60210.10050.01281.38244.4141.2499-1.4318-4.7233-1.8071-0.70142.61010.75940.2639-0.02420.23670.8243139.4697-107.7534-50.1782
83.79794.52724.84297.36988.75523.0942-1.76672.43940.9009-2.17692.91691.0760.05021.7182-0.4741.3746-0.78840.50161.98910.94860.8665116.3659-120.7159-58.3216
98.66196.9655-4.47349.5691-2.71546.1769-3.38390.3888-1.2331-2.79121.5218-1.7023-0.9778-2.13991.54233.9613-0.44150.55950.94820.23730.3202107.7859-132.9647-53.3727
103.4468-0.1717-0.73232.26240.4551.0967-0.27430.95270.0741-1.43340.672-0.02781.43590.2117-0.47382.2442-0.9794-0.03391.22730.0880.341488.7392-144.4204-38.5468
112.4296-2.0249-0.7244.6439-1.77393.0346-0.7890.18370.82961.5834-1.1735-0.19390.7035-0.1015-1.48570.8366-0.8661-0.30631.26911.3306-1.007667.0893-139.0334-52.4328
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN B AND RESID 452:531
3X-RAY DIFFRACTION3CHAIN B AND RESID 532:604
4X-RAY DIFFRACTION4CHAIN B AND RESID 605:692
5X-RAY DIFFRACTION5CHAIN B AND RESID 153:449
6X-RAY DIFFRACTION6CHAIN C AND (RESID 255:291 OR RESID 1003)
7X-RAY DIFFRACTION7CHAIN C AND (RESID 292:332 OR RESID 1001)
8X-RAY DIFFRACTION8CHAIN C AND (RESID 333:357 OR RESID 1002)
9X-RAY DIFFRACTION9CHAIN C AND RESID 358:376
10X-RAY DIFFRACTION10CHAIN C AND RESID 377:643
11X-RAY DIFFRACTION11CHAIN C AND RESID 644:692

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