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- PDB-4gid: Structure of beta-secretase complexed with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4gid
TitleStructure of beta-secretase complexed with inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / ASPARTIC PROTEASE / BETA SECRETASE / APP / BACE / A-BETA / PROTEASE / MEMAPSIN / ALZHEIMER / DRUG DESIGN / 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 / 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 / protein serine/threonine kinase binding / 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 / aspartic-type endopeptidase activity / lysosome / 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-0GH / L-PROLINAMIDE / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsGhosh, A. / Tang, J. / Venkateswara, R.K. / Yadav, N. / Anderson, D. / Gavande, N. / Huang, X. / Terzyan, S.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Structure-based design of highly selective beta-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.
Authors: Ghosh, A.K. / Venkateswara Rao, K. / Yadav, N.D. / Anderson, D.D. / Gavande, N. / Huang, X. / Terzyan, S. / Tang, J.
History
DepositionAug 8, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 10, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2013Group: 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
C: Beta-secretase 1
D: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)176,14312
Polymers173,0234
Non-polymers3,1208
Water21,9601219
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0363
Polymers43,2561
Non-polymers7802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0363
Polymers43,2561
Non-polymers7802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0363
Polymers43,2561
Non-polymers7802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0363
Polymers43,2561
Non-polymers7802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.427, 130.353, 88.401
Angle α, β, γ (deg.)90.00, 97.50, 90.00
Int Tables number4
Space group name H-MP1211

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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: 43255.754 Da / Num. of mol.: 4 / Fragment: CATALYTIC DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pET11a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P56817, memapsin 2
#2: Chemical
ChemComp-0GH / N-[(2S)-1-({(2S,3R)-3-hydroxy-1-[(2-methylpropyl)amino]-1-oxobutan-2-yl}amino)-3-phenylpropan-2-yl]-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide


Mass: 665.843 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C35H47N5O6S
#3: Chemical
ChemComp-LPD / L-PROLINAMIDE


Type: L-peptide linking / Mass: 114.146 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C5H10N2O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1219 / 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: 2.85 Å3/Da / Density % sol: 56.89 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 12% PEG 8000, NA CACODYLATE BUFFER, 15MG/ML PROTEIN CONCENTRATION, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 290K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Aug 24, 2010 / Details: VariMax HR optic
RadiationMonochromator: VariMax HR optic / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 130808 / Num. obs: 130546 / % possible obs: 99.8 % / Observed criterion σ(I): -3

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2VKM

2vkm


Resolution: 2→34.49 Å / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2519 8766 -random
Rwork0.2156 ---
obs0.2156 124360 95.1 %-
all-130745 --
Solvent computationSolvent model: Bulk solvent correction / Bsol: 60.4332 Å2 / ksol: 0.359501 e/Å3
Displacement parametersBiso mean: 28.8 Å2
Baniso -1Baniso -2Baniso -3
1-5.182 Å20 Å23.62 Å2
2--8.446 Å20 Å2
3----13.628 Å2
Refinement stepCycle: LAST / Resolution: 2→34.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12178 0 220 1219 13617
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_deg0.011985
X-RAY DIFFRACTIONc_angle_d1.751
X-RAY DIFFRACTIONc_mcbond_it0.778
X-RAY DIFFRACTIONc_mcangle_it1.36

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