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- PDB-6nv9: BACE1 in complex with a macrocyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 6nv9
TitleBACE1 in complex with a macrocyclic inhibitor
ComponentsBeta-secretase 1
KeywordsPEPTIDE BINDING PROTEIN / protease / 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-L3M / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 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 4, 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)132,4539
Polymers130,2783
Non-polymers2,1756
Water11,097616
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1513
Polymers43,4261
Non-polymers7252
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1513
Polymers43,4261
Non-polymers7252
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1513
Polymers43,4261
Non-polymers7252
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.194, 103.052, 101.470
Angle α, β, γ (deg.)90.00, 104.23, 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-L3M / (3S)-3-hydroxy-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: 628.865 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H52N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 616 / 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: 3.2 Å3/Da / Density % sol: 61.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2 M MgSO4 0.1 M Na citrate 14-20 % PEG 4000 / 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 / Detector: PIXEL / Date: Aug 18, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.13→98 Å / Num. obs: 91867 / % possible obs: 99 % / Redundancy: 3.8 % / CC1/2: 0.995 / Rpim(I) all: 0.046 / Net I/σ(I): 10.7
Reflection shellResolution: 2.13→2.2 Å / Mean I/σ(I) obs: 2.4 / CC1/2: 0.785 / Rpim(I) all: 0.334 / % possible all: 100

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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: 2.13→79.67 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.81
RfactorNum. reflection% reflection
Rfree0.1902 1999 2.18 %
Rwork0.1551 --
obs0.1559 91791 99.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.13→79.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8780 0 147 616 9543
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0129161
X-RAY DIFFRACTIONf_angle_d1.28912436
X-RAY DIFFRACTIONf_dihedral_angle_d13.7563273
X-RAY DIFFRACTIONf_chiral_restr0.0611340
X-RAY DIFFRACTIONf_plane_restr0.0061590
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1257-2.17890.25871420.21466381X-RAY DIFFRACTION100
2.1789-2.23780.27821430.20326442X-RAY DIFFRACTION100
2.2378-2.30360.24921430.19176390X-RAY DIFFRACTION100
2.3036-2.3780.2081430.17836437X-RAY DIFFRACTION100
2.378-2.4630.21441430.18316413X-RAY DIFFRACTION100
2.463-2.56160.25481430.17386412X-RAY DIFFRACTION100
2.5616-2.67820.20321430.17366439X-RAY DIFFRACTION100
2.6782-2.81940.20961430.17876420X-RAY DIFFRACTION100
2.8194-2.99610.23071430.17076463X-RAY DIFFRACTION100
2.9961-3.22740.20321430.16596411X-RAY DIFFRACTION100
3.2274-3.55220.1741440.15546441X-RAY DIFFRACTION100
3.5522-4.06620.19491420.13626420X-RAY DIFFRACTION99
4.0662-5.12280.12551440.11736439X-RAY DIFFRACTION99
5.1228-79.72620.18081400.15016284X-RAY DIFFRACTION96
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)
10.9351-0.16990.1923.19941.19482.7013-0.22220.08920.4385-0.334-0.01210.3027-0.4644-0.2450.23550.50440.0474-0.07430.36750.02430.3637-15.179-14.010724.2037
22.16690.24840.12172.49780.6991.9993-0.1446-0.29720.42280.26090.02810.1211-0.3329-0.22360.12210.45010.0892-0.03030.3501-0.04870.3135-14.5321-13.454635.9786
32.4866-0.44830.67643.57230.22692.6264-0.0833-0.0529-0.0409-0.1320.15230.1881-0.0719-0.22020.00170.2678-0.03390.03860.25720.03170.1873-11.8463-31.917526.8416
42.5617-0.5985-0.55573.6510.07633.1633-0.1729-0.2359-0.2510.2440.1741-0.55740.20190.2944-0.07740.2576-0.0115-0.04990.2728-0.01210.32984.7879-36.494531.2583
52.8807-0.0505-1.07952.89320.36372.75860.1569-0.2050.0478-0.23570.1036-1.3044-0.62060.8164-0.14120.3715-0.12750.06860.4396-0.12750.749315.9514-27.663925.1926
63.59161.6096-0.6274.0679-0.28512.4869-0.15060.34420.3679-0.510.2795-0.3814-0.42230.1186-0.13810.406-0.04740.08310.3028-0.00560.35545.8038-29.744918.126
73.73850.3409-0.08322.71420.24931.5644-0.0926-0.0005-0.0823-0.00760.1447-0.3322-0.13210.1011-0.02960.354-0.03430.01550.2251-0.01110.2264-4.2415-29.447928.2332
83.110.1506-0.23283.68281.15490.798-0.03470.1835-0.0581-0.11870.0615-0.4001-0.12270.1429-0.02010.3083-0.03680.0510.3011-0.01250.2824-2.8344-38.911123.1648
93.9655-0.40230.86442.0001-0.26032.91520.16750.504-0.3473-0.2513-0.132-0.23780.17950.8973-0.02180.29110.04980.00840.5336-0.06690.314817.1771-11.184258.5316
103.375-1.23010.51052.348-0.09673.71870.0001-0.4982-0.96090.18760.20090.40530.4968-0.1248-0.06280.2822-0.005-0.03170.2830.10950.5215-3.2044-17.518673.5497
112.8753-0.16580.08360.77680.06063.2950.1281-0.0767-1.0650.1015-0.05360.2430.7036-0.066-0.0530.332-0.0125-0.04630.23070.01710.6161-6.2135-19.236369.3049
123.5529-0.458-0.58791.841-0.80493.12720.0109-0.1572-0.5802-0.05110.12060.15490.1231-0.2978-0.15360.29370.0073-0.01180.26280.02260.4066-8.3553-9.201670.5459
131.25640.2313-0.56822.0514-0.60133.33530.03470.0217-0.14390.0514-0.01760.13550.4043-0.4337-0.01060.3001-0.036-0.04660.32140.01240.311633.9061-24.148991.519
142.2507-0.0767-0.70523.5444-1.34033.43920.2388-0.27280.5260.59590.0920.0447-0.7881-0.0892-0.24160.41710.02270.09130.3097-0.01950.342744.18533.343694.3684
151.73520.5926-0.39923.0163-0.52472.58140.1913-0.02980.26630.21260.04380.2617-0.3135-0.3067-0.21530.27230.05820.04150.33750.05040.327940.9429-2.160987.2128
161.45091.4242-0.8453.07010.31312.32240.0569-0.02130.0414-0.0057-0.00960.001-0.19150.0374-0.08770.30530.06150.04570.3250.03450.335947.519-6.406780.6336
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 168 )
3X-RAY DIFFRACTION3chain 'A' and (resid 169 through 202 )
4X-RAY DIFFRACTION4chain 'A' and (resid 203 through 233 )
5X-RAY DIFFRACTION5chain 'A' and (resid 234 through 267 )
6X-RAY DIFFRACTION6chain 'A' and (resid 268 through 322 )
7X-RAY DIFFRACTION7chain 'A' and (resid 323 through 349 )
8X-RAY DIFFRACTION8chain 'A' and (resid 350 through 385 )
9X-RAY DIFFRACTION9chain 'B' and (resid -1 through 168 )
10X-RAY DIFFRACTION10chain 'B' and (resid 169 through 270 )
11X-RAY DIFFRACTION11chain 'B' and (resid 271 through 346 )
12X-RAY DIFFRACTION12chain 'B' and (resid 347 through 386 )
13X-RAY DIFFRACTION13chain 'C' and (resid -1 through 202 )
14X-RAY DIFFRACTION14chain 'C' and (resid 203 through 276 )
15X-RAY DIFFRACTION15chain 'C' and (resid 277 through 346 )
16X-RAY DIFFRACTION16chain 'C' and (resid 347 through 385 )

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