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- PDB-6od6: Structure of BACE-1 in complex with Ligand 13 -

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Basic information

Entry
Database: PDB / ID: 6od6
TitleStructure of BACE-1 in complex with Ligand 13
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 / 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-M7D / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsShaffer, P.L.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Evaluation of a Series of beta-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.
Authors: Oehlrich, D. / Peschiulli, A. / Tresadern, G. / Van Gool, M. / Vega, J.A. / De Lucas, A.I. / Alonso de Diego, S.A. / Prokopcova, H. / Austin, N. / Van Brandt, S. / Surkyn, M. / De Cleyn, M. ...Authors: Oehlrich, D. / Peschiulli, A. / Tresadern, G. / Van Gool, M. / Vega, J.A. / De Lucas, A.I. / Alonso de Diego, S.A. / Prokopcova, H. / Austin, N. / Van Brandt, S. / Surkyn, M. / De Cleyn, M. / Vos, A. / Rombouts, F.J.R. / Macdonald, G. / Moechars, D. / Gijsen, H.J.M. / Trabanco, A.A.
History
DepositionMar 26, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_unobs_or_zero_occ_atoms
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)145,5917
Polymers144,3333
Non-polymers1,2574
Water6,557364
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,5002
Polymers48,1111
Non-polymers3881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,5923
Polymers48,1111
Non-polymers4802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,5002
Polymers48,1111
Non-polymers3881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)232.398, 100.391, 64.606
Angle α, β, γ (deg.)90.00, 103.67, 90.00
Int Tables number5
Space group name H-MC121

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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-M7D / N-{3-[(3R)-1-amino-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-3-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide


Mass: 388.398 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C21H17FN6O / References: memapsin 2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 364 / 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: 2.54 Å3/Da / Density % sol: 56.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.25 / Details: 17% PEG-4000, 0.1M MES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99986 Å
DetectorType: DECTRIS PILATUS 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: 2→112.91 Å / Num. obs: 97044 / % possible obs: 97.8 % / Observed criterion σ(I): 0 / Redundancy: 2.9 % / Biso Wilson estimate: 46.44 Å2 / Rmerge(I) obs: 0.028 / Net I/σ(I): 9.6
Reflection shellResolution: 2→2.19 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.406 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 22722 / % possible all: 98.1

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260: ???)refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→48.255 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 31.35
RfactorNum. reflection% reflectionSelection details
Rfree0.2478 1033 1.09 %RANDOM
Rwork0.223 ---
obs0.2233 94945 97.59 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2→48.255 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8845 0 93 364 9302
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0039259
X-RAY DIFFRACTIONf_angle_d0.70112605
X-RAY DIFFRACTIONf_dihedral_angle_d13.4795397
X-RAY DIFFRACTIONf_chiral_restr0.0481356
X-RAY DIFFRACTIONf_plane_restr0.0041648
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0001-2.10550.3721520.387113235X-RAY DIFFRACTION97
2.1055-2.23740.34871480.331313528X-RAY DIFFRACTION99
2.2374-2.41020.2761480.281213517X-RAY DIFFRACTION99
2.4102-2.65270.28211500.2613433X-RAY DIFFRACTION98
2.6527-3.03650.29041470.249913504X-RAY DIFFRACTION98
3.0365-3.82540.29081450.217113432X-RAY DIFFRACTION97
3.8254-48.26920.18841430.183313263X-RAY DIFFRACTION95
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)
10.0073-0.0037-0.00620.00130.00360.00750.10880.08860.1222-0.11180.0392-0.0246-0.1892-0.008600.39180.00310.04580.1894-0.03990.2654-27.2398-62.129914.7488
20.0234-0.00610.00480.01240.00350.01530.02240.00010.166-0.08080.0020.04080.0086-0.0068-00.3296-0.0414-0.0660.2657-0.02380.3479-45.5508-55.491910.3601
30.002-0.00310.00030.0029-0.00150.00310.0138-0.01910.02440.00890.0404-0.0026-0.02780.0291-00.46780.0020.03760.4787-0.20490.6075-51.8955-45.993119.5296
40.0023-0.0019-0.00180.0006-0.00140.00130.00610.0006-0.01770.01140.0108-0.01560.01710.0155-00.8566-0.1050.20020.8126-0.04580.7811-17.7966-87.5079-7.3604
50.0310.0299-0.00710.06090.0210.0195-0.17540.42080.1311-0.68230.0719-0.675-0.35660.702400.17430.00220.16280.267-0.32370.252-16.0716-79.19427.306
60.0034-0.00110.00660.00140.0007-0.0011-0.05010.0015-0.059-0.0041-0.0112-0.02050.09650.0029-00.50080.1196-0.19090.42-0.18860.6765-12.0775-83.955619.1954
70.00180.0003-0.00170.00220.00090.00350.0088-0.0223-0.01910.0582-0.0070.00050.0598-0.0028-00.52230.1514-0.05450.5760.00660.5461-74.2528-26.942744.7421
80.0196-0.02250.01640.03470.03750.0337-0.03240.3125-0.2695-0.3017-0.04480.01820.3648-0.001800.92420.2781-0.50440.8076-0.5530.6987-74.024-38.036331.9648
90.0004-0.0044-0.00050.00210.00270.00080.0059-0.01120.00740.00860.006-0.0152-0.0145-0.0001-01.04770.2062-0.19410.9168-0.2680.9423-65.7695-48.580330.2105
100.2875-0.04720.17590.29750.09420.1682-0.2977-0.24840.78510.0646-0.0749-0.0016-0.0782-0.190800.43490.022-0.1190.5195-0.17660.603-22.3275-46.771428.2198
110.03310.04010.1510.32460.1583-0.00080.34310.4308-0.51310.24690.1468-0.50370.03490.5836-0-0.70961.53551.1417-2.2964-1.9886-1.1994-27.052-104.22221.7461
120.0749-0.0950.09190.26720.18230.06530.02961.2286-0.4853-0.20710.3848-0.21790.42090.1707-0-0.4380.99540.7521-0.4252-1.0337-0.3267-53.4414-25.591546.2122
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -5 through 11 )
2X-RAY DIFFRACTION2chain 'A' and (resid 12 through 63 )
3X-RAY DIFFRACTION3chain 'A' and (resid 64 through 80 )
4X-RAY DIFFRACTION4chain 'B' and (resid 1 through 11 )
5X-RAY DIFFRACTION5chain 'B' and ((resid 12 through 63 ) or (resid 81 through 146))
6X-RAY DIFFRACTION6chain 'B' and (resid 64 through 80 )
7X-RAY DIFFRACTION7chain 'C' and (resid 1 through 11 )
8X-RAY DIFFRACTION8chain 'C' and ((resid 12 through 63 ) or (resid 81 through 146))
9X-RAY DIFFRACTION9chain 'C' and (resid 64 through 80 )
10X-RAY DIFFRACTION10chain 'A' and (resid 147 through 385)
11X-RAY DIFFRACTION11chain 'B' and (resid 147 through 385)
12X-RAY DIFFRACTION12chain 'C' and (resid 147 through 385)

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