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- PDB-4h1e: Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl... -

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Basic information

Entry
Database: PDB / ID: 4h1e
TitleStructure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BACE1 / Alzheimers / 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-10J / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsOrth, P.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation.
Authors: Mandal, M. / Zhu, Z. / Cumming, J.N. / Liu, X. / Strickland, C. / Mazzola, R.D. / Caldwell, J.P. / Leach, P. / Grzelak, M. / Hyde, L. / Zhang, Q. / Terracina, G. / Zhang, L. / Chen, X. / ...Authors: Mandal, M. / Zhu, Z. / Cumming, J.N. / Liu, X. / Strickland, C. / Mazzola, R.D. / Caldwell, J.P. / Leach, P. / Grzelak, M. / Hyde, L. / Zhang, Q. / Terracina, G. / Zhang, L. / Chen, X. / Kuvelkar, R. / Kennedy, M.E. / Favreau, L. / Cox, K. / Orth, P. / Buevich, A. / Voigt, J. / Wang, H. / Kazakevich, I. / McKittrick, B.A. / Greenlee, W. / Parker, E.M. / Stamford, A.W.
History
DepositionSep 10, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 17, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2012Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,4114
Polymers92,5002
Non-polymers9112
Water9,350519
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7052
Polymers46,2501
Non-polymers4561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7052
Polymers46,2501
Non-polymers4561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.212, 89.936, 131.323
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Beta-secretase 1 / / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta- ...Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 46249.926 Da / Num. of mol.: 2 / Fragment: UNP Residues 41-454
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: Bl21(de3) / Gene: BACE, BACE1, KIAA1149 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-10J / 3-{5-[(2E,4aR,7aR)-6-benzoyl-2-imino-3-methyl-4-oxooctahydro-7aH-pyrrolo[3,4-d]pyrimidin-7a-yl]thiophen-3-yl}benzonitrile


Mass: 455.532 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H21N5O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 519 / 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: 2.75 Å3/Da / Density % sol: 55.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 15% PEG 3350, 200mM Na/K tartrate, 100mM Hepes pH7, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Dec 8, 2011
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 81486 / Num. obs: 80509 / % possible obs: 98.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.4 % / Rmerge(I) obs: 0.111 / Χ2: 1.124 / Net I/σ(I): 11.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
1.9-1.973.80.6461.673770.89291.5
1.97-2.054.20.5032.379621.01898.7
2.05-2.144.40.394379911.14399.6
2.14-2.254.50.3043.580461.1899.8
2.25-2.394.50.2394.280951.19799.9
2.39-2.584.60.1974.880911.21399.9
2.58-2.844.60.1575.781201.23599.9
2.84-3.254.60.1236.881291.22599.9
3.25-4.094.60.0938.682371.05199.7
4.09-504.40.06713.584611.00899.1

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Processing

Software
NameVersionClassificationNB
BUSTER-TNTBUSTER 2.11.1refinement
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
CNSphasing
BUSTER2.11.1refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1M4H

1m4h


Resolution: 1.9→31.37 Å / Cor.coef. Fo:Fc: 0.9251 / Cor.coef. Fo:Fc free: 0.9074 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2968 3250 4.05 %RANDOM
Rwork0.2602 ---
all0.2617 81039 --
obs0.2617 80237 99.01 %-
Displacement parametersBiso max: 116.2 Å2 / Biso mean: 36.1965 Å2 / Biso min: 18 Å2
Baniso -1Baniso -2Baniso -3
1-7.5178 Å20 Å20 Å2
2---13.4792 Å20 Å2
3---5.9614 Å2
Refine analyzeLuzzati coordinate error obs: 0.311 Å
Refinement stepCycle: LAST / Resolution: 1.9→31.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6023 0 66 519 6608
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2045SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes159HARMONIC2
X-RAY DIFFRACTIONt_gen_planes922HARMONIC5
X-RAY DIFFRACTIONt_it6255HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion795SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7563SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6255HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8521HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.62
X-RAY DIFFRACTIONt_other_torsion15.62
LS refinement shellResolution: 1.9→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2944 217 3.94 %
Rwork0.2657 5292 -
all0.2668 5509 -
obs--99.01 %

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