[English] 日本語
Yorodumi
- PDB-2p4j: Crystal structure of beta-secretase bond to an inhibitor with Iso... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 2p4j
TitleCrystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3
ComponentsBeta-secretase 1
KeywordsHYDROLASE / beta-secretase / memapsin / BACE / asp / aspartic protease / acid protease / Alzheimer's disease / drug design / structure based 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 / 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 / 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-23I / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsHong, L. / Ghosh, A.K. / Tang, J.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands.
Authors: Ghosh, A.K. / Kumaragurubaran, N. / Hong, L. / Kulkarni, S.S. / Xu, X. / Chang, W. / Weerasena, V. / Turner, R. / Koelsch, G. / Bilcer, G. / Tang, J.
History
DepositionMar 12, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 24, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Revision 1.4Aug 30, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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)176,0598
Polymers173,2514
Non-polymers2,8084
Water7,891438
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0152
Polymers43,3131
Non-polymers7021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0152
Polymers43,3131
Non-polymers7021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0152
Polymers43,3131
Non-polymers7021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0152
Polymers43,3131
Non-polymers7021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.929, 129.969, 87.483
Angle α, β, γ (deg.)90.00, 97.48, 90.00
Int Tables number4
Space group name H-MP1211

-
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


Mass: 43312.805 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 / 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-23I / N-[(1S,2S,4R)-2-HYDROXY-1-ISOBUTYL-5-({(1S)-1-[(ISOPROPYLAMINO)CARBONYL]-2-METHYLPROPYL}AMINO)-4-METHYL-5-OXOPENTYL]-5-[METHYL(METHYLSULFONYL)AMINO]-N'-[(1R)-1-PHENYLETHYL]ISOPHTHALAMIDE


Mass: 701.916 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C36H55N5O7S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 438 / 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: 2.83 Å3/Da / Density % sol: 56.49 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: CRYSTALLIZATION CONDITIONS: APO ENZYME CRYSTAL WAS OBTAINED AT 15 mg/ml, 13% PEG 8000, PH 6.5 IN SODIUM CACODYLATE BUFFER. THE APO ENZYME CRYSTAL WAS SOAKED IN CONCENTRATED INHIBITOR ...Details: CRYSTALLIZATION CONDITIONS: APO ENZYME CRYSTAL WAS OBTAINED AT 15 mg/ml, 13% 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

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Jul 3, 2006 / Details: mirrors
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: 2.5→50 Å / Num. all: 66606 / Num. obs: 66290 / % possible obs: 97.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.9 % / Rmerge(I) obs: 0.11 / Χ2: 1.065 / Net I/σ(I): 8.1
Reflection shellResolution: 2.5→2.59 Å / Rmerge(I) obs: 0.611 / Mean I/σ(I) obs: 1.9 / Num. unique all: 5760 / Χ2: 1.029 / % possible all: 85.6

-
Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT2data extraction
MAR345dtbdata collection
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1FKN
Resolution: 2.5→50 Å / FOM work R set: 0.793 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.259 4989 7.5 %Random
Rwork0.201 ---
obs0.201 60825 91.3 %-
all-66606 --
Solvent computationBsol: 37.395 Å2
Displacement parametersBiso mean: 38.821 Å2
Baniso -1Baniso -2Baniso -3
1-2.558 Å20 Å23.689 Å2
2--9.528 Å20 Å2
3----12.086 Å2
Refinement stepCycle: LAST / Resolution: 2.5→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12212 0 196 438 12846
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.0087821.5
X-RAY DIFFRACTIONc_angle_deg1.546312
X-RAY DIFFRACTIONc_mcbond_it1.4282
X-RAY DIFFRACTIONc_mcangle_it2.4752.5
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 50

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs
2.5-2.520.398760.341849925
2.52-2.530.343760.315895971
2.53-2.550.34660.333893959
2.55-2.570.344910.324898989
2.57-2.590.348950.2989051000
2.59-2.610.35840.2849641048
2.61-2.630.3281000.2969441044
2.63-2.650.403910.3069731064
2.65-2.670.3281010.2929961097
2.67-2.690.379970.3019801077
2.69-2.720.292910.26610521143
2.72-2.740.286830.26710561139
2.74-2.760.33890.27710691158
2.76-2.790.303870.26711061193
2.79-2.820.334940.26610611155
2.82-2.840.364790.25111341213
2.84-2.870.2581040.24410771181
2.87-2.90.2991000.23811561256
2.9-2.930.34970.24410871184
2.93-2.960.292850.23511331218
2.96-30.3241080.22911321240
3-3.030.3371110.25111321243
3.03-3.070.3411090.24111461255
3.07-3.110.3131130.22511451258
3.11-3.150.3161190.23511171236
3.15-3.190.2791130.21411921305
3.19-3.240.3281200.22811281248
3.24-3.290.305880.21611681256
3.29-3.340.2651220.20711811303
3.34-3.390.285960.21511711267
3.39-3.450.2431190.211481267
3.45-3.510.2521070.19612301337
3.51-3.580.2451010.19111731274
3.58-3.650.272950.18912391334
3.65-3.730.2531140.19512061320
3.73-3.820.2121110.16612091320
3.82-3.920.211910.17112021293
3.92-4.020.2041040.1612231327
4.02-4.140.201910.16312081299
4.14-4.270.1971150.14211991314
4.27-4.430.1931170.14612171334
4.43-4.60.2051210.15112291350
4.6-4.810.237970.15312091306
4.81-5.070.2041000.15312131313
5.07-5.380.266960.18412281324
5.38-5.80.2691090.20712251334
5.8-6.380.2431080.19811941302
6.38-7.30.2281100.19412221332
7.3-9.190.2421010.19812271328
9.19-500.221970.18110951192
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2mmi327.par
X-RAY DIFFRACTION3water_rep.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