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- PDB-6nco: Fragment-based Discovery of an apoE4 Stabilizer -

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Basic information

Entry
Database: PDB / ID: 6nco
TitleFragment-based Discovery of an apoE4 Stabilizer
ComponentsApolipoprotein E
KeywordsLIPID TRANSPORT / Lipid Binding
Function / homology
Function and homology information


chylomicron remnant / lipid transport involved in lipid storage / triglyceride-rich lipoprotein particle clearance / intermediate-density lipoprotein particle clearance / positive regulation of lipid transport across blood-brain barrier / positive regulation of heparan sulfate proteoglycan binding / regulation of cellular response to very-low-density lipoprotein particle stimulus / metal chelating activity / Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors / discoidal high-density lipoprotein particle ...chylomicron remnant / lipid transport involved in lipid storage / triglyceride-rich lipoprotein particle clearance / intermediate-density lipoprotein particle clearance / positive regulation of lipid transport across blood-brain barrier / positive regulation of heparan sulfate proteoglycan binding / regulation of cellular response to very-low-density lipoprotein particle stimulus / metal chelating activity / Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors / discoidal high-density lipoprotein particle / chylomicron remnant clearance / lipoprotein particle / intermediate-density lipoprotein particle / maintenance of location in cell / very-low-density lipoprotein particle clearance / very-low-density lipoprotein particle remodeling / regulation of amyloid-beta clearance / response to caloric restriction / Chylomicron clearance / negative regulation of triglyceride metabolic process / NMDA glutamate receptor clustering / chylomicron / phosphatidylcholine-sterol O-acyltransferase activator activity / Chylomicron remodeling / positive regulation of phospholipid efflux / lipid transporter activity / Chylomicron assembly / positive regulation of cholesterol metabolic process / positive regulation of low-density lipoprotein particle receptor catabolic process / regulation of behavioral fear response / high-density lipoprotein particle remodeling / phospholipid efflux / high-density lipoprotein particle clearance / multivesicular body, internal vesicle / lipoprotein catabolic process / very-low-density lipoprotein particle receptor binding / regulation of amyloid fibril formation / AMPA glutamate receptor clustering / regulation of protein metabolic process / low-density lipoprotein particle / cholesterol transfer activity / reverse cholesterol transport / positive regulation by host of viral process / high-density lipoprotein particle assembly / very-low-density lipoprotein particle / positive regulation of amyloid-beta clearance / lipoprotein biosynthetic process / melanosome organization / positive regulation of CoA-transferase activity / protein import / negative regulation of blood coagulation / low-density lipoprotein particle remodeling / high-density lipoprotein particle / negative regulation of amyloid fibril formation / amyloid precursor protein metabolic process / negative regulation of cholesterol biosynthetic process / triglyceride homeostasis / regulation of Cdc42 protein signal transduction / heparan sulfate proteoglycan binding / regulation of amyloid precursor protein catabolic process / cholesterol catabolic process / HDL remodeling / positive regulation of membrane protein ectodomain proteolysis / synaptic transmission, cholinergic / negative regulation of endothelial cell migration / cholesterol efflux / Scavenging by Class A Receptors / negative regulation of protein metabolic process / artery morphogenesis / triglyceride metabolic process / regulation of axon extension / regulation of cholesterol metabolic process / positive regulation of amyloid fibril formation / low-density lipoprotein particle receptor binding / positive regulation of dendritic spine development / virion assembly / regulation of innate immune response / regulation of neuronal synaptic plasticity / locomotory exploration behavior / lipoprotein particle binding / negative regulation of amyloid-beta formation / positive regulation of endocytosis / antioxidant activity / negative regulation of endothelial cell proliferation / cGMP-mediated signaling / response to dietary excess / negative regulation of blood vessel endothelial cell migration / negative regulation of long-term synaptic potentiation / negative regulation of platelet activation / positive regulation of cholesterol efflux / positive regulation of dendritic spine maintenance / intracellular transport / regulation of protein-containing complex assembly / negative regulation of protein secretion / long-term memory / fatty acid homeostasis / long-chain fatty acid transport / synaptic cleft / positive regulation of lipid biosynthetic process / Nuclear signaling by ERBB4
Similarity search - Function
Apolipoprotein / Apolipoprotein A/E / Apolipoprotein A1/A4/E domain / Four Helix Bundle (Hemerythrin (Met), subunit A) / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-KQP / Apolipoprotein E
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.707 Å
AuthorsJakob, C.G. / Qiu, W.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer.
Authors: Petros, A.M. / Korepanova, A. / Jakob, C.G. / Qiu, W. / Panchal, S.C. / Wang, J. / Dietrich, J.D. / Brewer, J.T. / Pohlki, F. / Kling, A. / Wilcox, K. / Lakics, V. / Bahnassawy, L. / ...Authors: Petros, A.M. / Korepanova, A. / Jakob, C.G. / Qiu, W. / Panchal, S.C. / Wang, J. / Dietrich, J.D. / Brewer, J.T. / Pohlki, F. / Kling, A. / Wilcox, K. / Lakics, V. / Bahnassawy, L. / Reinhardt, P. / Partha, S.K. / Bodelle, P.M. / Lake, M. / Charych, E.I. / Stoll, V.S. / Sun, C. / Mohler, E.G.
History
DepositionDec 11, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2019Provider: repository / Type: Initial release
Revision 1.1May 8, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Oct 11, 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Apolipoprotein E
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,8662
Polymers21,5231
Non-polymers3431
Water2,720151
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.960, 52.870, 86.440
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Apolipoprotein E / / Apo-E


Mass: 21523.221 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APOE / Production host: Escherichia coli (E. coli) / References: UniProt: P02649
#2: Chemical ChemComp-KQP / 1-[5-chloro-4'-(2-hydroxypropan-2-yl)[1,1'-biphenyl]-3-yl]cyclobutane-1-carboximidamide


Mass: 342.862 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23ClN2O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2.17 Å3/Da / Density % sol: 43.43 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop
Details: 20% w/v Polyethylene glycol monomethyl ether mesylate 5,000; 0.1M Bis-Tris buffer at pH6.5

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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 PILATUS 6M / Detector: PIXEL / Date: Feb 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.707→45.105 Å / Num. obs: 20917 / % possible obs: 99.5 % / Redundancy: 5.8 % / Rmerge(I) obs: 0.053 / Net I/σ(I): 17.6
Reflection shellResolution: 1.707→1.737 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.469 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 972 / % possible all: 98.1

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260: ???)refinement
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1GS9

1gs9


Resolution: 1.707→33.462 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 23.52
RfactorNum. reflection% reflection
Rfree0.22 1007 4.8 %
Rwork0.1931 --
obs0.1944 20914 99.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.707→33.462 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1164 0 24 151 1339
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071268
X-RAY DIFFRACTIONf_angle_d1.2931719
X-RAY DIFFRACTIONf_dihedral_angle_d8.1561087
X-RAY DIFFRACTIONf_chiral_restr0.283187
X-RAY DIFFRACTIONf_plane_restr0.004223
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6977-1.78710.42041490.3332712X-RAY DIFFRACTION95
1.7871-1.89910.27631440.23152838X-RAY DIFFRACTION100
1.8991-2.04570.25331460.20812881X-RAY DIFFRACTION100
2.0457-2.25160.24071560.19372863X-RAY DIFFRACTION100
2.2516-2.57730.20051290.18212935X-RAY DIFFRACTION100
2.5773-3.24660.22481600.19662893X-RAY DIFFRACTION100
3.2466-33.46850.18841330.17873065X-RAY DIFFRACTION99

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