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- PDB-6nw3: BACE1 in complex with a macrocyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 6nw3
TitleBACE1 in complex with a macrocyclic inhibitor
ComponentsBeta-secretase 1
KeywordsPEPTIDE BINDING PROTEIN/Inhibitor / protease / inhibitor complex / PEPTIDE BINDING PROTEIN / PEPTIDE BINDING 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 / cellular response to manganese ion / prepulse inhibition / amyloid-beta metabolic process ...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 / cellular response to manganese ion / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / multivesicular body / response to lead ion / trans-Golgi network / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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-L4J / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.352 Å
AuthorsYen, Y.C. / Ghosh, A.K. / Mesecar, A.D.
Funding support United States, 1items
OrganizationGrant numberCountry
Department of Health & Human Services (HHS) United States
CitationJournal: Biochemistry / Year: 2019
Title: Development of an Efficient Enzyme Production and Structure-Based Discovery Platform for BACE1 Inhibitors.
Authors: Yen, Y.C. / Kammeyer, A.M. / Jensen, K.C. / Tirlangi, J. / Ghosh, A.K. / Mesecar, A.D.
History
DepositionFeb 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)132,59711
Polymers130,2783
Non-polymers2,3198
Water10,611589
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,2314
Polymers43,4261
Non-polymers8053
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3275
Polymers43,4261
Non-polymers9014
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0392
Polymers43,4261
Non-polymers6131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.455, 102.356, 99.513
Angle α, β, γ (deg.)90.00, 105.01, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 43425.961 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-L4J / N-(2-methylpropyl)-N~2~-{[(4S)-17-[(methylsulfonyl)(propyl)amino]-2-oxo-3-azatricyclo[13.3.1.1~6,10~]icosa-1(19),6(20),7,9,15,17-hexaen-4-yl]methyl}-L-norleucinamide


Mass: 612.866 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H52N4O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 589 / 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: 3.08 Å3/Da / Density % sol: 60.01 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 0.2 M MgSO4 0.1 M Na citrate 14-20 % PEG4000 / PH range: 5-6

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS3 R CdTe 300K-W / Detector: PIXEL / Date: Oct 27, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.35→20 Å / Num. obs: 65032 / % possible obs: 99 % / Redundancy: 3.8 % / CC1/2: 1 / Rpim(I) all: 0.04 / Net I/σ(I): 13.7
Reflection shellResolution: 2.35→2.44 Å / Mean I/σ(I) obs: 2.1 / CC1/2: 0.768 / Rpim(I) all: 0.375 / % possible all: 98.7

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6NV7

6nv7


Resolution: 2.352→20 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.94
RfactorNum. reflection% reflection
Rfree0.2131 3224 5.06 %
Rwork0.1834 --
obs0.1849 63697 97.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.352→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8811 0 154 589 9554
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0069211
X-RAY DIFFRACTIONf_angle_d0.97112507
X-RAY DIFFRACTIONf_dihedral_angle_d14.7493294
X-RAY DIFFRACTIONf_chiral_restr0.0461346
X-RAY DIFFRACTIONf_plane_restr0.0041596
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3524-2.38750.3211030.25341979X-RAY DIFFRACTION73
2.3875-2.42470.3141210.25582369X-RAY DIFFRACTION87
2.4247-2.46440.27221350.2322467X-RAY DIFFRACTION92
2.4644-2.50680.28641370.22872553X-RAY DIFFRACTION96
2.5068-2.55230.24961290.2272655X-RAY DIFFRACTION97
2.5523-2.60130.27421500.22372617X-RAY DIFFRACTION98
2.6013-2.65430.27781610.2122631X-RAY DIFFRACTION99
2.6543-2.71190.27551520.21222684X-RAY DIFFRACTION99
2.7119-2.77480.24061340.2122673X-RAY DIFFRACTION100
2.7748-2.8440.2651630.21192711X-RAY DIFFRACTION100
2.844-2.92070.26341180.19392695X-RAY DIFFRACTION100
2.9207-3.00630.23011280.19092699X-RAY DIFFRACTION100
3.0063-3.1030.23491620.18532680X-RAY DIFFRACTION100
3.103-3.21350.20171610.18542680X-RAY DIFFRACTION100
3.2135-3.34160.21751220.18382700X-RAY DIFFRACTION100
3.3416-3.49290.23081300.17262713X-RAY DIFFRACTION100
3.4929-3.6760.20891510.17332704X-RAY DIFFRACTION100
3.676-3.90480.18961390.1582690X-RAY DIFFRACTION100
3.9048-4.20370.17691450.15652716X-RAY DIFFRACTION100
4.2037-4.6220.17271700.14892688X-RAY DIFFRACTION100
4.622-5.28010.1671480.1522721X-RAY DIFFRACTION100
5.2801-6.61230.18161280.18782746X-RAY DIFFRACTION100
6.6123-20.02280.18421370.18952702X-RAY DIFFRACTION97

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