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- PDB-2vkm: Crystal structure of GRL-8234 bound to BACE (Beta-secretase) -

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Basic information

Entry
Database: PDB / ID: 2vkm
TitleCrystal structure of GRL-8234 bound to BACE (Beta-secretase)
ComponentsBETA-SECRETASE 1
KeywordsHYDROLASE / ALTERNATIVE SPLICING / ASPARTYL PROTEASE / ASPARTIC PROTEASE / GLYCOPROTEIN / TRANSMEMBRANE / BETA SECRETASE / APP / BACE / A-BETA / X- RAY / ZYMOGEN / MEMBRANE / PROTEASE / MEMAPSIN / ALZHEIMER / DRUG DESIGN
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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / 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 / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / 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-BSD / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsHong, L. / Tang, J. / Ghosh, A.K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Potent Memapsin 2 (Beta-Secretase) Inhibitors: Design, Synthesis, Protein-Ligand X-Ray Structure, and in Vivo Evaluation.
Authors: Ghosh, A.K. / Kumaragurubaran, N. / Hong, L. / Kulkarni, S. / Xu, X. / Miller, H.B. / Reddy, D.S. / Weerasena, V. / Turner, R. / Chang, W. / Koelsch, G. / Tang, J.
History
DepositionDec 4, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 16, 2008Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf
Revision 1.4Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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)175,8868
Polymers173,2514
Non-polymers2,6354
Water14,124784
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
MethodPQS
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
MethodPQS
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
MethodPQS
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
MethodPQS
Unit cell
Length a, b, c (Å)86.704, 130.308, 87.711
Angle α, β, γ (deg.)90.00, 97.41, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper: (Code: given / Matrix: (1), (1), (1))

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Components

#1: Protein
BETA-SECRETASE 1 / BETA-SITE APP CLEAVING ENZYME 1 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / MEMBRANE- ...BETA-SITE APP CLEAVING ENZYME 1 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / MEMBRANE-ASSOCIATED ASPARTIC PROTEASE 2 / MEMAPSIN-2 / ASPARTYL PROTEASE 2 / ASP 2 / ASP2 / BACE


Mass: 43312.805 Da / Num. of mol.: 4 / Fragment: BETA-SECRETASE CATALYTIC DOMAIN, RESIDUES 58-446
Source method: isolated from a genetically manipulated source
Details: BETA SECRETASE INHIBITOR / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: P56817
#2: Chemical
ChemComp-BSD / N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide


Mass: 658.807 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C36H42N4O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 784 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Nonpolymer detailsN-(R-CARBOXY-ETHYL)-ALPHA-(S)-(2-PHENYLETHYL)GLYCYL-L-ARGININE-N-PHE

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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: 2.9 Å3/Da / Density % sol: 56 % / Description: NONE
Crystal growpH: 6.5
Details: 12% PEG 8000, NACACODYLATE BUFFER, PH 6.5. 15MG/ML PROTEIN CONCENTRATION. ROOM TEMPERATURE.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jan 30, 2005 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 119992 / % possible obs: 99 % / Observed criterion σ(I): 0 / Redundancy: 3.9 % / Biso Wilson estimate: 17.2 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 17
Reflection shellResolution: 2.01→2.12 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 2.7 / % possible all: 95

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Processing

Software
NameVersionClassification
CNS1refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1FKN

1fkn


Resolution: 2.05→50 Å / Rfactor Rfree error: 0.003 / Data cutoff high absF: 10000 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: MLF
RfactorNum. reflection% reflectionSelection details
Rfree0.2418 9156 7.6 %RANDOM
Rwork0.2016 ---
obs0.2016 113913 94.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.5921 Å2 / ksol: 0.378055 e/Å3
Displacement parametersBiso mean: 29.4 Å2
Baniso -1Baniso -2Baniso -3
1-2.717 Å20 Å22.956 Å2
2--5.072 Å20 Å2
3----7.789 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.27 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.05→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12212 0 188 784 13184
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d25.5
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.93
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.391.5
X-RAY DIFFRACTIONc_mcangle_it2.212
X-RAY DIFFRACTIONc_scbond_it2.042
X-RAY DIFFRACTIONc_scangle_it2.922.5
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.011 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.317 836 8.2 %
Rwork0.273 9419 -
obs--47 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2INH.PARINH.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP

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