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- PDB-6e3z: Structure of Bace-1 in complex with Ligand 8 -

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Basic information

Entry
Database: PDB / ID: 6e3z
TitleStructure of Bace-1 in complex with Ligand 8
ComponentsBeta-secretase 1
KeywordsHYDROLASE/INHIBITOR / bace protease / hydrolase / HYDROLASE-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 / amyloid-beta metabolic process / prepulse inhibition ...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 / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / 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 / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / 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-HRV / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsShaffer, P.L.
CitationJournal: Acs Symp.Ser. / Year: 2020
Title: Discovery and Chemical Development of JNJ-50138803, a Clinical Candidate BACE1 Inhibitor
Authors: Gijsen, H.J.M. / Lin, J. / Houpis, Y.
History
DepositionJul 16, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 25, 2020Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.title / _citation.year

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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)146,1947
Polymers144,3333
Non-polymers1,8614
Water14,772820
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,5762
Polymers48,1111
Non-polymers4651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,5762
Polymers48,1111
Non-polymers4651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,0423
Polymers48,1111
Non-polymers9302
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)232.178, 100.500, 63.968
Angle α, β, γ (deg.)90.000, 103.220, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-629-

HOH

21A-692-

HOH

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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: 48111.129 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 (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical
ChemComp-HRV / N-{3-[(2R,3R)-5-amino-3-methyl-2-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl}-3,5-dichloropyridine-2-carboxamide


Mass: 465.229 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H14Cl2F4N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 820 / 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: 2.52 Å3/Da / Density % sol: 51.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.25 / Details: 17% PEG-4000, 0.1 M MES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99986 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 19, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99986 Å / Relative weight: 1
ReflectionResolution: 1.94→49.451 Å / Num. obs: 104486 / % possible obs: 98.8 % / Redundancy: 4.13 % / Biso Wilson estimate: 33.42 Å2 / Rmerge F obs: 0.096 / Rmerge(I) obs: 0.044 / Rrim(I) all: 0.051 / Χ2: 1.067 / Net I/σ(I): 18.16 / Num. measured all: 431560 / Scaling rejects: 204
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRrim(I) all% possible all
1.94-2.144.1930.4053.7263820.46398.3
2.14-2.464.130.1767.92264520.20299
2.46-34.2010.07117.14230400.08199
3-3.84.0810.03332.62144670.03799
3.8-4.883.8180.02442.9874020.02898.5
4.88-7.124.1520.01857.3145490.02199.4
7.12-11.393.8660.01663.7916470.01999.2
11.39-49.4514.2960.01572.645470.01796.8

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIX1.13.2998refinement
PDB_EXTRACT3.24data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.94→49.451 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.2
RfactorNum. reflection% reflection
Rfree0.2125 860 0.82 %
Rwork0.179 --
obs0.1793 104468 98.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 115.43 Å2 / Biso mean: 47.1521 Å2 / Biso min: 22.61 Å2
Refinement stepCycle: final / Resolution: 1.94→49.451 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8877 0 120 820 9817
Biso mean--50.1 48.96 -
Num. residues----1130
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.94-2.06160.34851410.2781170341717598
2.0616-2.22080.25871430.2308172441738799
2.2208-2.44420.27791430.2109172251736899
2.4442-2.79790.21981430.1945173081745199
2.7979-3.52490.22251440.1771172911743599
3.5249-49.46690.16551460.1492175061765299
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)
14.44040.31990.9861.23170.06441.318-0.08430.3990.3606-0.08130.03360.0719-0.01270.04350.0330.2647-0.0510.01230.26250.01880.2059-43.8154-55.236312.8568
24.0510.82011.46311.69280.44821.4790.0879-0.42030.21510.158-0.07590.01270.0901-0.233-0.01450.253-0.02820.02650.2456-0.0010.2113-31.5408-54.050628.9507
33.96880.22560.55252.21330.17682.119-0.1030.33421.0587-0.0982-0.0599-0.0436-0.37140.00260.14030.2625-0.0079-0.06570.27920.06320.5238-17.861-38.89223.9335
43.4990.960.87752.6925-0.48061.90390.0083-0.3670.24850.3342-0.00840.0465-0.0555-0.1411-0.01550.2631-0.0028-0.01590.2708-0.01890.2527-22.8134-51.482430.9374
51.24070.87850.13572.85990.58972.7738-0.15410.4677-0.0411-0.88440.4667-0.7943-0.26480.4216-0.31150.4936-0.10050.22230.4794-0.1270.6176-16.9912-83.4702-0.5374
61.3027-0.2569-0.33022.84151.11181.7306-0.16720.2251-0.3137-0.27960.5957-1.5193-0.02320.617-0.36680.3839-0.04930.0950.4727-0.24110.8737-11.462-78.839210.0806
71.17751.03620.70424.80091.71461.25280.0358-0.02460.06910.0253-0.0252-0.108-0.00960.0763-0.00290.27070.03120.0430.3039-0.06320.2893-29.1117-93.60165.9414
81.13730.73190.20483.17870.86172.27880.1410.0458-0.33780.23030.1937-0.73480.34940.4837-0.20750.3440.102-0.0490.3765-0.14730.5286-21.8177-112.2121.0929
91.79920.5021.61413.25660.52891.63220.02920.039-0.117-0.03240.1074-0.30940.11010.1258-0.06560.27150.02460.05580.2895-0.09420.3028-28.9888-102.48721.0197
100.6491-0.317-0.32670.79370.91481.36020.5560.6545-0.9033-0.5232-0.24210.80020.6285-0.0666-0.0690.84280.2409-0.44840.6504-0.35230.8319-73.5819-37.638532.1036
112.5339-0.70670.82272.40780.46491.88370.42870.6469-0.3441-0.3102-0.1989-0.14210.29010.2656-0.19480.38390.1775-0.01220.4213-0.12220.2883-54.8126-26.890243.2953
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid -4 through 116 )A-4 - 116
2X-RAY DIFFRACTION2chain 'A' and (resid 117 through 233 )A117 - 233
3X-RAY DIFFRACTION3chain 'A' and (resid 234 through 322 )A234 - 322
4X-RAY DIFFRACTION4chain 'A' and (resid 323 through 385 )A323 - 385
5X-RAY DIFFRACTION5chain 'B' and (resid -3 through 41 )B-3 - 41
6X-RAY DIFFRACTION6chain 'B' and (resid 42 through 116 )B42 - 116
7X-RAY DIFFRACTION7chain 'B' and (resid 117 through 233 )B117 - 233
8X-RAY DIFFRACTION8chain 'B' and (resid 234 through 309 )B234 - 309
9X-RAY DIFFRACTION9chain 'B' and (resid 317 through 385 )B317 - 385
10X-RAY DIFFRACTION10chain 'C' and (resid -6 through 106 )C-6 - 106
11X-RAY DIFFRACTION11chain 'C' and (resid 107 through 385 )C107 - 385

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