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- PDB-5qcr: Crystal structure of BACE complex with BMC026 -

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Basic information

Entry
Database: PDB / ID: 5qcr
TitleCrystal structure of BACE complex with BMC026
ComponentsBeta-secretase 1
KeywordsHYDROLASE / Hydroloase / D3R / BACE / Ligand Docking
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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / 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-E4J / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
Model detailsStructures for D3R docking challenge
AuthorsRondeau, J.M. / Shao, C. / Yang, H. / Burley, S.K.
CitationJournal: J.Comput.Aided Mol.Des. / Year: 2020
Title: D3R grand challenge 4: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies.
Authors: Parks, C.D. / Gaieb, Z. / Chiu, M. / Yang, H. / Shao, C. / Walters, W.P. / Jansen, J.M. / McGaughey, G. / Lewis, R.A. / Bembenek, S.D. / Ameriks, M.K. / Mirzadegan, T. / Burley, S.K. / Amaro, R.E. / Gilson, M.K.
History
DepositionDec 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 3, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: Structure summary / Category: audit_author / Item: _audit_author.identifier_ORCID
Revision 1.2Feb 10, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.3Nov 13, 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
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)136,1169
Polymers134,3323
Non-polymers1,7846
Water5,675315
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3723
Polymers44,7771
Non-polymers5952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3723
Polymers44,7771
Non-polymers5952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3723
Polymers44,7771
Non-polymers5952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.761, 102.757, 99.928
Angle α, β, γ (deg.)90.00, 103.28, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
31

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection details
111CHAIN A
211CHAIN B
311CHAIN C

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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: 44777.336 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-E4J / 2-(butylamino)-N-[(2S,3S,5R)-6-(butylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-6-methoxypyridine-4-carboxamide


Mass: 498.657 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C28H42N4O4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 315 / 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: 3.04 Å3/Da / Density % sol: 59.56 %
Crystal growTemperature: 292 K / Method: hanging drop
Details: CRYSTALS WERE GROWN AT 19C BY VAPOUR DIFFUSION IN HANGING DROPS USING 1.0M UNBUFFERED AMMONIUM SULFATE AS PRECIPITANT. PROTEIN STOCK WAS BACE MUT46B BATCH IX 8.1MG/ML IN 10MM TRIS-HCL PH 7. ...Details: CRYSTALS WERE GROWN AT 19C BY VAPOUR DIFFUSION IN HANGING DROPS USING 1.0M UNBUFFERED AMMONIUM SULFATE AS PRECIPITANT. PROTEIN STOCK WAS BACE MUT46B BATCH IX 8.1MG/ML IN 10MM TRIS-HCL PH 7.4, 25MM NACL WITH A 4-FOLD EXCESS OF BMC026 ADDED FROM A 100MM STOCK SOLUTION IN DMSO. CRYO-PROTECTANT WAS 2.0M LI2SO4, 2%(V/V) PEG 400, 0.1M CITRATE PH 5.5, 0.5MM BMC026, 1% DMSO.

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9795
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jul 31, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.2→46.52 Å / Num. obs: 81413 / % possible obs: 99.7 % / Rmerge(I) obs: 0.059

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIX1.12_2829refinement
CNXrefinement
CNXphasing
SCALEPACKdata scaling
DENZOdate reduction
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→46.52 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 20.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.205 8170 10.04 %
Rwork0.173 --
obs0.176 81413 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51 Å2
Refinement stepCycle: LAST / Resolution: 2.2→46.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8859 0 123 315 9297
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0089219
X-RAY DIFFRACTIONf_angle_d0.98112528
X-RAY DIFFRACTIONf_dihedral_angle_d16.0875373
X-RAY DIFFRACTIONf_chiral_restr0.0641353
X-RAY DIFFRACTIONf_plane_restr0.0071608
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDType
11A5405X-RAY DIFFRACTIONPOSITIONAL
12B5405X-RAY DIFFRACTIONPOSITIONAL
13C5405X-RAY DIFFRACTIONPOSITIONAL
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2001-2.22510.26412490.20342288X-RAY DIFFRACTION93
2.2251-2.25130.24652900.19272408X-RAY DIFFRACTION100
2.2513-2.27870.23852900.18222445X-RAY DIFFRACTION100
2.2787-2.30760.22772730.19232402X-RAY DIFFRACTION100
2.3076-2.3380.26032860.19242432X-RAY DIFFRACTION100
2.338-2.370.25442630.19292428X-RAY DIFFRACTION100
2.37-2.40380.23812800.20142446X-RAY DIFFRACTION100
2.4038-2.43970.23742650.1952444X-RAY DIFFRACTION100
2.4397-2.47780.26432660.19582486X-RAY DIFFRACTION100
2.4778-2.51850.2412650.18182413X-RAY DIFFRACTION100
2.5185-2.56190.20962750.18092456X-RAY DIFFRACTION100
2.5619-2.60850.24522630.18432409X-RAY DIFFRACTION100
2.6085-2.65860.23312570.1892466X-RAY DIFFRACTION100
2.6586-2.71290.2442840.19482431X-RAY DIFFRACTION100
2.7129-2.77190.24052510.20212470X-RAY DIFFRACTION100
2.7719-2.83630.26082750.20732436X-RAY DIFFRACTION100
2.8363-2.90730.23262780.19752436X-RAY DIFFRACTION100
2.9073-2.98590.23232940.19912422X-RAY DIFFRACTION100
2.9859-3.07370.24012400.19222473X-RAY DIFFRACTION100
3.0737-3.17290.23892840.19862447X-RAY DIFFRACTION100
3.1729-3.28630.23082620.19682442X-RAY DIFFRACTION100
3.2863-3.41780.20692750.19362468X-RAY DIFFRACTION100
3.4178-3.57330.20472600.17262474X-RAY DIFFRACTION100
3.5733-3.76160.19422670.1542442X-RAY DIFFRACTION100
3.7616-3.99720.15962720.13792445X-RAY DIFFRACTION100
3.9972-4.30560.16272790.13582456X-RAY DIFFRACTION100
4.3056-4.73850.14373060.12252430X-RAY DIFFRACTION100
4.7385-5.42330.16912640.14342482X-RAY DIFFRACTION100
5.4233-6.82930.21452950.18452457X-RAY DIFFRACTION100
6.8293-46.53010.20732620.19172509X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
10.1546-0.2175-0.22270.75290.08740.4168-0.1371-0.33370.24480.30630.037-0.2205-0.10540.104-0.00010.454-0.0099-0.06220.3344-0.03130.348843.767110.30225.1917
20.5836-0.15750.21030.68810.00570.34340.0410.1650.3765-0.2976-0.04820.0382-0.18610.0191-0.00010.5021-0.0382-0.00390.31130.0740.415741.0817.377111.3284
30.8736-0.06610.40562.0071-0.28430.84130.00250.11870.1437-0.0022-0.0361-0.1472-0.1520.0709-0.00010.3627-0.0330.00580.30490.01410.239243.69915.036617.2717
40.4183-0.245-0.13520.9101-0.1850.8453-0.02880.0905-0.0196-0.17230.10340.3737-0.0184-0.03270.00020.33670.0077-0.04670.34540.01930.367124.0534-9.818816.9791
50.51250.37860.11310.9589-0.53990.65990.02590.03180.14610.23120.16740.27160.0144-0.13140.00710.27190.02790.10220.29040.03410.383819.8516-6.631829.4121
60.83470.1736-0.22970.332-0.07920.14480.00650.08540.27620.1625-0.02870.381-0.18380.0151-0.00050.41020.05710.04740.306-0.00770.46722.24242.578728.6962
70.57860.03420.45841.2411-0.42090.5226-0.0541-0.2307-0.10750.34270.03260.1205-0.30690.15720.00050.40460.04380.07010.27760.00470.275936.699-8.48829.1601
80.303-0.2837-0.03030.305-0.03580.06720.04930.0282-0.3149-0.1597-0.06620.35530.0571-0.29610.00070.40670.0141-0.02870.3878-0.03870.363230.1565-20.440216.8869
90.42640.03240.11840.4914-0.17830.10160.1293-0.4137-0.17630.2934-0.1661-0.08460.0748-0.24800.3907-0.0225-0.01240.52450.05180.321717.544411.2228-2.4292
100.7319-0.43850.22610.40790.14090.7688-0.0331-0.1564-0.4959-0.0609-0.14520.22970.141-0.3928-0.00010.2755-0.05230.03430.49990.02030.47863.706910.7317-10.1007
111.3752-0.01990.64820.788-0.24020.98670.0714-0.1662-0.08190.0345-0.18850.2377-0.1101-0.3858-0.00020.30250.01-0.00780.43-0.01820.33169.548915.6425-11.1048
120.98620.3383-0.24390.56840.43070.6467-0.0151-0.1747-0.25980.1864-0.0582-0.1269-0.07010.0467-00.3211-0.0001-0.04470.33720.06120.261529.821619.1512-8.084
131.13190.39460.21060.7419-0.54560.6716-0.18440.2508-0.2992-0.26110.14680.07240.0557-0.0897-00.30470.00370.00350.3022-0.0620.329530.26959.2422-28.9071
140.4392-0.0902-0.14330.4785-0.10890.7682-0.06460.1477-0.364-0.1479-0.1244-0.39160.14990.2686-0.15890.29470.08750.02880.1783-0.01150.561636.4625-0.4772-20.9525
150.3332-0.0812-0.02680.27210.12240.196600.1354-0.3505-0.0029-0.0964-0.12610.3032-0.2352-0.00750.4453-0.0175-0.04280.2730.00020.594728.0269-2.922-17.027
161.43060.6393-0.28730.55170.39461.07940.0356-0.0259-0.2764-0.0316-0.0765-0.11240.09980.0468-0.00830.28930.0203-0.04040.30660.0630.384135.891515.8518-19.0783
170.26310.0812-0.37020.3363-0.29070.61330.13170.0953-0.1904-0.0716-0.06110.21460.1109-0.4726-0.00060.2857-0.0371-0.01070.4870.04730.4303-1.1328-48.434437.3401
180.46640.0736-0.19230.9926-0.1450.98840.1029-0.3333-0.09760.2841-0.13350.15830.1505-0.0592-0.00040.3695-0.05830.02610.40320.12060.38342.6314-56.252450.9377
190.99780.3794-0.24880.9438-0.29041.0565-0.0075-0.0171-0.1906-0.01250.0694-0.03290.1999-0.153900.32790.0175-0.0180.33180.06280.35898.0644-50.263337.7109
201.1986-0.0765-0.38510.4759-0.24670.31460.2153-0.29560.04070.2133-0.1514-0.0919-0.07710.1529-0.00010.3631-0.0367-0.00050.38350.00430.35122.188-31.534142.6923
210.9120.6392-0.16380.7325-0.62451.23420.1758-0.01240.23760.28840.03110.1758-0.1881-0.05620.03050.2930.03550.12760.2585-0.01140.34629.0667-22.858941.4699
221.11040.537-0.65460.336-0.41951.23390.0859-0.01810.0830.09-0.083-0.0891-0.1305-0.0517-0.00010.28320.0358-0.01510.30710.03620.300317.5385-34.767532.7473
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID -2 THROUGH 32 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 33 THROUGH 74 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 75 THROUGH 192 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 193 THROUGH 251 )
5X-RAY DIFFRACTION5CHAIN 'A' AND (RESID 252 THROUGH 301 )
6X-RAY DIFFRACTION6CHAIN 'A' AND (RESID 302 THROUGH 340 )
7X-RAY DIFFRACTION7CHAIN 'A' AND (RESID 341 THROUGH 368 )
8X-RAY DIFFRACTION8CHAIN 'A' AND (RESID 369 THROUGH 385 )
9X-RAY DIFFRACTION9CHAIN 'B' AND (RESID -2 THROUGH 32 )
10X-RAY DIFFRACTION10CHAIN 'B' AND (RESID 33 THROUGH 74 )
11X-RAY DIFFRACTION11CHAIN 'B' AND (RESID 75 THROUGH 143 )
12X-RAY DIFFRACTION12CHAIN 'B' AND (RESID 144 THROUGH 192 )
13X-RAY DIFFRACTION13CHAIN 'B' AND (RESID 193 THROUGH 251 )
14X-RAY DIFFRACTION14CHAIN 'B' AND (RESID 252 THROUGH 309 )
15X-RAY DIFFRACTION15CHAIN 'B' AND (RESID 310 THROUGH 340 )
16X-RAY DIFFRACTION16CHAIN 'B' AND (RESID 341 THROUGH 385 )
17X-RAY DIFFRACTION17CHAIN 'C' AND (RESID -2 THROUGH 32 )
18X-RAY DIFFRACTION18CHAIN 'C' AND (RESID 33 THROUGH 85 )
19X-RAY DIFFRACTION19CHAIN 'C' AND (RESID 86 THROUGH 192 )
20X-RAY DIFFRACTION20CHAIN 'C' AND (RESID 193 THROUGH 251 )
21X-RAY DIFFRACTION21CHAIN 'C' AND (RESID 252 THROUGH 327 )
22X-RAY DIFFRACTION22CHAIN 'C' AND (RESID 328 THROUGH 385 )

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