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- PDB-2p83: Potent and selective isophthalamide S2 hydroxyethylamine inhibito... -

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Basic information

Entry
Database: PDB / ID: 2p83
TitlePotent and selective isophthalamide S2 hydroxyethylamine inhibitor of BACE1
ComponentsBeta-secretase 1
KeywordsHYDROLASE / protein-inhibitor complex
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / neuronal cell body / dendrite / Golgi apparatus / enzyme binding / cell surface / proteolysis / membrane / plasma membrane
Similarity search - Function
Beta-secretase BACE1 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Beta-secretase BACE1 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-MR0 / PHOSPHATE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsBenson, T.E. / Prince, D.B. / Tomasselli, A.G. / Emmons, T.L. / Paddock, D.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Potent and selective isophthalamide S(2) hydroxyethylamine inhibitors of BACE1.
Authors: Kortum, S.W. / Benson, T.E. / Bienkowski, M.J. / Emmons, T.L. / Prince, D.B. / Paddock, D.J. / Tomasselli, A.G. / Moon, J.B. / Laborde, A. / Tenbrink, R.E.
History
DepositionMar 21, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2007Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2007Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.4Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,96410
Polymers150,7523
Non-polymers2,2127
Water2,918162
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,0514
Polymers50,2511
Non-polymers8013
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,9563
Polymers50,2511
Non-polymers7062
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,9563
Polymers50,2511
Non-polymers7062
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.960, 103.350, 101.010
Angle α, β, γ (deg.)90.00, 104.12, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Beta-secretase 1 / Beta-site APP cleaving enzyme 1 / Beta-site amyloid protein cleaving enzyme 1 / Membrane-associated ...Beta-site APP cleaving enzyme 1 / Beta-site amyloid protein cleaving enzyme 1 / Membrane-associated aspartic protease 2 / Memapsin-2 / Aspartyl protease 2 / Asp 2 / ASP2


Mass: 50250.586 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-MR0 / N~3~-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-N~1~,N~1~-DIPROPYLBENZENE-1,3,5-TRICARBOXAMIDE


Mass: 610.691 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C33H40F2N4O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / Source method: isolated from a natural source / Formula: H2O
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

CrystalDensity Matthews: 2.75 Å3/Da / Density % sol: 55.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.6
Details: 1.0M ammonium phosphate, 0.1M ammonium citrate , pH 5.6, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jun 30, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 50632 / % possible obs: 87.4 % / Rmerge(I) obs: 0.061 / Χ2: 1.246 / Net I/σ(I): 10.9
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
2.5-2.590.33345830.30379.2
2.59-2.690.26945250.35778.9
2.69-2.820.21345540.43878.7
2.82-2.960.16245780.57179
2.96-3.150.11946510.76481.1
3.15-3.390.09450321.11786.8
3.39-3.730.0754581.46394.3
3.73-4.270.05956692.0698
4.27-5.380.04957742.2399.1
5.38-500.03858081.82698.1

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT2data extraction
HKL-2000data reduction
X-PLORphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→20 Å / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.242 4757 8.4 %
Rwork0.207 --
obs-47284 83.7 %
Displacement parametersBiso mean: 45.734 Å2
Baniso -1Baniso -2Baniso -3
1--1.832 Å20 Å2-2.382 Å2
2---4.709 Å20 Å2
3---6.542 Å2
Refinement stepCycle: LAST / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8790 0 152 162 9104
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_d1.529
X-RAY DIFFRACTIONc_mcbond_it1.4241.5
X-RAY DIFFRACTIONc_scbond_it1.9712
X-RAY DIFFRACTIONc_mcangle_it2.4092
X-RAY DIFFRACTIONc_scangle_it2.9632.5
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.paramMSI_CNX_TOPPAR:protein.top
X-RAY DIFFRACTION2MSI_CNX_TOPPAR:dna-rna_rep.paramMSI_CNX_TOPPAR:dna-rna.top
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.paramMSI_CNX_TOPPAR:water.top
X-RAY DIFFRACTION4MSI_CNX_TOPPAR:ion.paramMSI_CNX_TOPPAR:ion.top
X-RAY DIFFRACTION5lig.parlig.top

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