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

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Basic information

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


lipid transport involved in lipid storage / intermediate-density lipoprotein particle clearance / positive regulation of lipid transport across blood-brain barrier / regulation of cellular response to very-low-density lipoprotein particle stimulus / metal chelating activity / triglyceride-rich lipoprotein particle clearance / discoidal high-density lipoprotein particle / lipoprotein particle / negative regulation of triglyceride metabolic process / negative regulation of cholesterol biosynthetic process ...lipid transport involved in lipid storage / intermediate-density lipoprotein particle clearance / positive regulation of lipid transport across blood-brain barrier / regulation of cellular response to very-low-density lipoprotein particle stimulus / metal chelating activity / triglyceride-rich lipoprotein particle clearance / discoidal high-density lipoprotein particle / lipoprotein particle / negative regulation of triglyceride metabolic process / negative regulation of cholesterol biosynthetic process / regulation of amyloid-beta clearance / positive regulation of lipoprotein transport / Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors / chylomicron remnant clearance / chylomicron remnant / intermediate-density lipoprotein particle / maintenance of location in cell / very-low-density lipoprotein particle remodeling / acylglycerol homeostasis / NMDA glutamate receptor clustering / phosphatidylcholine-sterol O-acyltransferase activator activity / response to caloric restriction / Chylomicron clearance / positive regulation of phospholipid efflux / very-low-density lipoprotein particle clearance / Chylomicron remodeling / lipid transporter activity / positive regulation of cholesterol metabolic process / regulation of behavioral fear response / cellular response to lipoprotein particle stimulus / positive regulation of low-density lipoprotein particle receptor catabolic process / regulation of amyloid fibril formation / Chylomicron assembly / : / high-density lipoprotein particle clearance / chylomicron / phospholipid efflux / regulation of protein metabolic process / very-low-density lipoprotein particle receptor binding / AMPA glutamate receptor clustering / high-density lipoprotein particle remodeling / lipoprotein catabolic process / melanosome organization / multivesicular body, internal vesicle / reverse cholesterol transport / positive regulation of amyloid-beta clearance / host-mediated activation of viral process / high-density lipoprotein particle assembly / low-density lipoprotein particle / protein import / lipoprotein biosynthetic process / cholesterol transfer activity / high-density lipoprotein particle / very-low-density lipoprotein particle / cholesterol catabolic process / low-density lipoprotein particle remodeling / heparan sulfate proteoglycan binding / regulation of Cdc42 protein signal transduction / amyloid precursor protein metabolic process / negative regulation of amyloid fibril formation / triglyceride homeostasis / regulation of amyloid precursor protein catabolic process / positive regulation of membrane protein ectodomain proteolysis / synaptic transmission, cholinergic / HDL remodeling / negative regulation of endothelial cell migration / cholesterol efflux / regulation of axon extension / regulation of cholesterol metabolic process / negative regulation of protein metabolic process / artery morphogenesis / Scavenging by Class A Receptors / triglyceride metabolic process / positive regulation of dendritic spine development / low-density lipoprotein particle receptor binding / positive regulation of amyloid fibril formation / regulation of innate immune response / virion assembly / negative regulation of amyloid-beta formation / negative regulation of endothelial cell proliferation / antioxidant activity / locomotory exploration behavior / positive regulation of endocytosis / lipoprotein particle binding / response to dietary excess / negative regulation of blood vessel endothelial cell migration / regulation of neuronal synaptic plasticity / negative regulation of long-term synaptic potentiation / negative regulation of platelet activation / positive regulation of dendritic spine maintenance / negative regulation of blood coagulation / positive regulation of cholesterol efflux / negative regulation of MAP kinase activity / long-term memory / negative regulation of protein secretion / fatty acid homeostasis / regulation of protein-containing complex assembly / synaptic cleft / long-chain fatty acid transport / intracellular transport
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
1-(3-chlorophenyl)cyclobutane-1-carboximidamide / Apolipoprotein E
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 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 1, 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.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 8, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 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)21,7322
Polymers21,5231
Non-polymers2091
Water2,324129
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)41.070, 52.790, 84.540
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-KJM / 1-(3-chlorophenyl)cyclobutane-1-carboximidamide


Mass: 208.687 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H13ClN2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 129 / 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: 2.13 Å3/Da / Density % sol: 42.23 %
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: Nov 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.82→36.94 Å / Num. obs: 14586 / % possible obs: 84.9 % / Redundancy: 6 % / Rmerge(I) obs: 0.043 / Net I/σ(I): 22.4
Reflection shellResolution: 1.82→1.85 Å / Rmerge(I) obs: 0.785 / Num. unique obs: 848 / % possible all: 100

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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: 1.82→36.94 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.41
RfactorNum. reflection% reflectionSelection details
Rfree0.2192 686 4.7 %Random selection
Rwork0.1836 ---
obs0.1852 14584 84.86 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.82→36.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1164 0 14 129 1307
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071216
X-RAY DIFFRACTIONf_angle_d0.8641637
X-RAY DIFFRACTIONf_dihedral_angle_d11.1471071
X-RAY DIFFRACTIONf_chiral_restr0.037178
X-RAY DIFFRACTIONf_plane_restr0.004220
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8166-1.95690.3306910.25911824X-RAY DIFFRACTION56
1.9569-2.15380.26541260.21392645X-RAY DIFFRACTION83
2.1538-2.46540.24121420.19543107X-RAY DIFFRACTION96
2.4654-3.10590.24651580.19392968X-RAY DIFFRACTION91
3.1059-36.94910.19131690.16813354X-RAY DIFFRACTION98

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