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- PDB-2g94: Crystal structure of beta-secretase bound to a potent and highly ... -

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Basic information

Entry
Database: PDB / ID: 2g94
TitleCrystal structure of beta-secretase bound to a potent and highly selective inhibitor.
ComponentsBeta-secretase 1
KeywordsHYDROLASE / beta secretase / Alzheimer's disease / memapsin / BACE / ASP2 / Aspartic protease / drug design / protease inhibitor
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 / 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 / recycling endosome / protein processing / 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 / lysosome / aspartic-type endopeptidase activity / 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-ZPQ / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsHong, L. / Ghosh, A. / Tang, J.
CitationJournal: J.Am.Chem.Soc. / Year: 2006
Title: Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors.
Authors: Ghosh, A.K. / Kumaragurubaran, N. / Hong, L. / Lei, H. / Hussain, K.A. / Liu, C.F. / Devasamudram, T. / Weerasena, V. / Turner, R. / Koelsch, G. / Bilcer, G. / Tang, J.
History
DepositionMar 5, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 25, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 30, 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
C: Beta-secretase 1
D: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,8878
Polymers173,2514
Non-polymers2,6354
Water15,367853
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9722
Polymers43,3131
Non-polymers6591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9722
Polymers43,3131
Non-polymers6591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9722
Polymers43,3131
Non-polymers6591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9722
Polymers43,3131
Non-polymers6591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.628, 131.024, 88.236
Angle α, β, γ (deg.)90.00, 97.39, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 43312.805 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE / Plasmid: pET11 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P56817, memapsin 2
#2: Chemical
ChemComp-ZPQ / N~2~-[(2R,4S,5S)-5-{[N-{[(3,5-DIMETHYL-1H-PYRAZOL-1-YL)METHOXY]CARBONYL}-3-(METHYLSULFONYL)-L-ALANYL]AMINO}-4-HYDROXY-2,7-DIMETHYLOCTANOYL]-N-ISOBUTYL-L-VALINAMIDE


Mass: 658.850 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H54N6O8S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 853 / 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: 2.87 Å3/Da / Density % sol: 57.07 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Apo enzyme crystal was obtained at 15% PEG 8000, PH 6.5 in Sodium Cacodylate buffer. The apo enzyme crystal was soaked in concentrated inhibitor solution to make the enzyme/inhibitor complex ...Details: Apo enzyme crystal was obtained at 15% PEG 8000, PH 6.5 in Sodium Cacodylate buffer. The apo enzyme crystal was soaked in concentrated inhibitor solution to make the enzyme/inhibitor complex crystal for X-ray data collection, VAPOR DIFFUSION, HANGING DROP, temperature 290K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Sep 19, 2003
RadiationMonochromator: Ni MIRROR + Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.86→46.38 Å / Num. all: 163375 / Num. obs: 161086 / % possible obs: 98.6 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 20.8 Å2 / Rmerge(I) obs: 0.068 / Net I/σ(I): 17.5
Reflection shellResolution: 1.86→1.93 Å / Rmerge(I) obs: 0.335 / Mean I/σ(I) obs: 3.4 / Num. unique all: 15349 / % possible all: 93.7

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Processing

Software
NameClassification
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1fkn

1fkn


Resolution: 1.86→46.38 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.227 12324 -random
Rwork0.199 ---
all0.199 163375 --
obs0.199 154719 94.7 %-
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.19 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 1.86→46.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12212 0 180 853 13245
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d25.3
X-RAY DIFFRACTIONc_improper_angle_d0.89
LS refinement shellResolution: 1.86→1.98 Å / Rfactor Rfree error: 0.007
RfactorNum. reflection% reflection
Rfree0.284 11836 -
Rwork0.259 --
obs-21285 85.2 %

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