[English] 日本語
Yorodumi
- PDB-3qbh: Structure based design, synthesis and SAR of cyclic hydroxyethyla... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 3qbh
TitleStructure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE Inhibitor / Enzyme inhibitor complex / HYDROLASE / 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-QBH / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.24 Å
AuthorsRondeau, J.M.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.
Authors: Rueeger, H. / Rondeau, J.M. / McCarthy, C. / Mobitz, H. / Tintelnot-Blomley, M. / Neumann, U. / Desrayaud, S.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Structure-Based Design of Macrocyclic Peptidomimetic beta-Secretase (BACE-1) Inhibitors
Authors: Machauer, R. / Veenstra, S. / Rondeau, J.M. / Tintelnot-Blomley, M. / Betschart, C. / Neumann, U. / Paganetti, P.
#2: Journal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo
Authors: Machauer, R. / Laumen, K. / Veenstra, S. / Rondeau, J.M. / Tintelnot-Blomley, M. / Betschart, C. / Jaton, A.-L. / Desrayaud, S. / Staufenbiel, M. / Rabe, S. / Paganetti, P. / Neumann, U.
#3: Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application
Authors: Lerchner, A. / Machauer, R. / Betschart, C. / Veenstra, S. / Rueeger, H. / McCarthy, C. / Tintelnot-Blomley, M. / Jaton, A.-L. / Rabe, S. / Desrayaud, S. / Enz, A. / Staufenbiel, M. / ...Authors: Lerchner, A. / Machauer, R. / Betschart, C. / Veenstra, S. / Rueeger, H. / McCarthy, C. / Tintelnot-Blomley, M. / Jaton, A.-L. / Rabe, S. / Desrayaud, S. / Enz, A. / Staufenbiel, M. / Paganetti, P. / Rondeau, J.M. / Neumann, U.
History
DepositionJan 13, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Mar 1, 2017Group: Other
Revision 1.3Oct 11, 2017Group: Data collection / Refinement description / Category: reflns_shell / software / Item: _reflns_shell.percent_possible_all

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,9666
Polymers134,3323
Non-polymers1,6343
Water9,026501
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3222
Polymers44,7771
Non-polymers5451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3222
Polymers44,7771
Non-polymers5451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3222
Polymers44,7771
Non-polymers5451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.003, 103.062, 100.904
Angle α, β, γ (deg.)90.000, 103.980, 90.000
Int Tables number4
Space group name H-MP1211

-
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: 44777.336 Da / Num. of mol.: 3 / Fragment: UNP residues 48-447
Source method: isolated from a genetically manipulated source
Details: Refolded / Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Plasmid: pET24 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-QBH / (4S)-4-(2-hydroxy-5-{[(3S,4S,5R)-4-hydroxy-1,1-dioxido-5-{[3-(propan-2-yl)benzyl]amino}tetrahydro-2H-thiopyran-3-yl]methyl}benzyl)-3-propyl-1,3-oxazolidin-2-one


Mass: 544.703 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C29H40N2O6S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 501 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 3.08 Å3/Da / Density % sol: 60.07 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 1.0M Ammonium phosphate, 0.1M sodium citrate pH 5.0, VAPOR DIFFUSION, HANGING DROP, temperature 292K

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97629 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 21, 2005
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97629 Å / Relative weight: 1
ReflectionResolution: 2.24→80 Å / Num. all: 78093 / Num. obs: 78093 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7.6 % / Biso Wilson estimate: 48.891 Å2 / Rmerge(I) obs: 0.063 / Net I/σ(I): 18.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique allNum. unique obs% possible all
2.24-2.337.30.3416631928617861799
2.33-2.47.60.3017450135908590899.9
2.4-2.487.60.2538.2451705919591999.9
2.48-2.567.60.19810.33968351965196100
2.56-2.667.60.163124348356915691100
2.66-2.767.70.13613.9374124882488299.9
2.76-2.887.70.10916.8383855010501099.9
2.88-3.017.70.08719.8350944576457699.9
3.01-3.167.70.07422.93378344104410100
3.16-3.357.70.06425.43410044474447100
3.35-3.567.60.05727.6300823937393799.8
3.56-3.837.60.05628.72912338153815100
3.83-4.167.60.05330.4263733463346399.8
4.16-4.597.60.0531.4238783139313999.8
4.59-5.27.60.04732.92175628652865100
5.2-6.147.60.04833.41882724822482100
6.14-7.877.50.04435.5152972030203099.8
7.87-12.270.03937.192641320132097
12.2-805.50.04232210838638673.5

-
Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
CNSrefinement
PDB_EXTRACT3.1data extraction
XDSdata reduction
CNXphasing
CNXrefinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.24→80 Å / Rfactor Rfree error: 0.002 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8558 / Data cutoff high absF: 2328977 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.219 7814 10 %RANDOM
Rwork0.197 ---
all0.2 78093 --
obs0.2 78093 99.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 51.9376 Å2 / ksol: 0.3693 e/Å3
Displacement parametersBiso max: 116.77 Å2 / Biso mean: 48.5611 Å2 / Biso min: 22.7 Å2
Baniso -1Baniso -2Baniso -3
1--2.88 Å20 Å2-0.1 Å2
2--6.86 Å20 Å2
3----3.98 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.26 Å
Luzzati d res low-5 Å
Luzzati sigma a0.26 Å0.2 Å
Refinement stepCycle: LAST / Resolution: 2.24→80 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8867 0 114 501 9482
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d29.1
X-RAY DIFFRACTIONc_improper_angle_d0.8
X-RAY DIFFRACTIONc_mcbond_it1.941.5
X-RAY DIFFRACTIONc_mcangle_it3.062
X-RAY DIFFRACTIONc_scbond_it2.842
X-RAY DIFFRACTIONc_scangle_it42.5
LS refinement shellResolution: 2.24→2.38 Å / Rfactor Rfree error: 0.002 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.277 1283 10 %
Rwork0.244 11608 -
all-12891 -
obs-12891 99.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3NVP-BGN587.PARAMION.TOP
X-RAY DIFFRACTION4CIS_PEPTIDE.PARAMNVP-BGN587.TOP
X-RAY DIFFRACTION5ION.PARAM

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more