[English] 日本語
Yorodumi
- PDB-8e2m: Bruton's tyrosine kinase (BTK) with compound 13 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8e2m
TitleBruton's tyrosine kinase (BTK) with compound 13
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / PROTEIN KINASE / INHIBITOR / COVALENT / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell ...regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of immunoglobulin production / positive regulation of B cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / mesoderm development / Fc-epsilon receptor signaling pathway / B cell activation / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / RHO GTPases Activate WASPs and WAVEs / positive regulation of phagocytosis / positive regulation of B cell proliferation / cell maturation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / apoptotic signaling pathway / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / calcium-mediated signaling / Regulation of actin dynamics for phagocytic cup formation / peptidyl-tyrosine phosphorylation / G beta:gamma signalling through BTK / positive regulation of interleukin-6 production / cellular response to reactive oxygen species / positive regulation of tumor necrosis factor production / G alpha (12/13) signalling events / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / protein tyrosine kinase activity / G alpha (q) signalling events / adaptive immune response / response to lipopolysaccharide / Potential therapeutics for SARS / intracellular signal transduction / protein phosphorylation / membrane raft / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase BTK, SH3 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / : / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain ...Tyrosine-protein kinase BTK, SH3 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / : / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
TRIETHYLENE GLYCOL / Chem-UB6 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.904 Å
AuthorsAlexander, R. / Milligan, C.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
Authors: Tichenor, M.S. / Wiener, J.J.M. / Rao, N.L. / Bacani, G.M. / Wei, J. / Pooley Deckhut, C. / Barbay, J.K. / Kreutter, K.D. / Chang, L. / Clancy, K.W. / Murrey, H.E. / Wang, W. / Ahn, K. / ...Authors: Tichenor, M.S. / Wiener, J.J.M. / Rao, N.L. / Bacani, G.M. / Wei, J. / Pooley Deckhut, C. / Barbay, J.K. / Kreutter, K.D. / Chang, L. / Clancy, K.W. / Murrey, H.E. / Wang, W. / Ahn, K. / Huber, M. / Rex, E. / Coe, K.J. / Wu, J. / Rui, H. / Sepassi, K. / Gaudiano, M. / Bekkers, M. / Cornelissen, I. / Packman, K. / Seierstad, M. / Xiouras, C. / Bembenek, S.D. / Alexander, R. / Milligan, C. / Balasubramanian, S. / Lebsack, A.D. / Venable, J.D. / Philippar, U. / Edwards, J.P. / Hirst, G.
History
DepositionAug 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2693
Polymers31,5981
Non-polymers6712
Water4,702261
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.155, 72.394, 103.946
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

-
Components

#1: Protein Tyrosine-protein kinase BTK / Agammaglobulinemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK / Bruton tyrosine kinase


Mass: 31598.287 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-UB6 / (5P)-5-[4-methyl-6-(2-methylpropyl)pyridin-3-yl]-4-oxo-N-[(1R,2S)-2-propanamidocyclopentyl]-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide


Mass: 520.646 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32N6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.27 Å3/Da / Density % sol: 45.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 25-33% PEG-5000 MME, 100 mM MES pH 6.35-6.75, 200 mM Ammonium Sulfate

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 23105 / % possible obs: 99.4 % / Redundancy: 4.3 % / Biso Wilson estimate: 14.66 Å2 / Rmerge(I) obs: 0.124 / Rpim(I) all: 0.065 / Rrim(I) all: 0.141 / Χ2: 1.076 / Net I/σ(I): 15.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.934.10.54311030.8350.290.6180.85198.4
1.93-1.9740.47911020.870.2540.5440.86798.3
1.97-2.014.30.4211560.9070.2140.4740.94399
2.01-2.054.50.4111040.9110.2040.460.90299.5
2.05-2.094.40.3711490.9190.1850.4150.91499.4
2.09-2.144.40.31911380.9450.160.3580.93999.6
2.14-2.194.40.28911390.960.1470.3250.97399.7
2.19-2.254.30.24411520.9610.1250.2750.9899.1
2.25-2.324.30.22111220.9690.1140.251.00499.5
2.32-2.3940.19411640.9670.1020.2211.0499.6
2.39-2.484.40.17211380.9790.0890.1950.99199.9
2.48-2.584.20.14511620.9840.0770.1651.01699.7
2.58-2.74.60.13811450.9850.070.1560.98599.4
2.7-2.844.50.12411440.9880.0640.141.00299.5
2.84-3.024.40.10711730.990.0560.1221.144100
3.02-3.254.30.0911520.990.0480.1031.27998.8
3.25-3.584.10.07411720.9920.040.0841.33899.2
3.58-4.094.20.0611850.9940.0330.0691.446100
4.09-5.164.30.05912150.9950.0320.0671.497100
5.16-503.90.05612900.9960.0310.0651.3899.1

-
Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.47 Å38.16 Å
Translation6.47 Å38.16 Å

-
Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.6.0phasing
PHENIX1.10_2155refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Internal Previously Solved BTK Structure

Resolution: 1.904→38.155 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 18.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1991 2000 8.67 %
Rwork0.1539 21063 -
obs0.1579 23063 99.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 78.01 Å2 / Biso mean: 18.945 Å2 / Biso min: 4.84 Å2
Refinement stepCycle: final / Resolution: 1.904→38.155 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2208 0 90 261 2559
Biso mean--24.53 27.72 -
Num. residues----270
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092410
X-RAY DIFFRACTIONf_angle_d0.873264
X-RAY DIFFRACTIONf_chiral_restr0.055336
X-RAY DIFFRACTIONf_plane_restr0.005415
X-RAY DIFFRACTIONf_dihedral_angle_d15.4931433
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.9044-1.9520.27471300.1871137793
1.952-2.00480.24051420.1711149399
2.0048-2.06380.24661390.1638146099
2.0638-2.13040.21671420.16241492100
2.1304-2.20650.21131410.1561488100
2.2065-2.29480.21791400.1594147499
2.2948-2.39930.19641440.15821524100
2.3993-2.52570.21081420.1541492100
2.5257-2.68390.2331430.15921505100
2.6839-2.89110.21061440.16631509100
2.8911-3.18190.19091440.159152399
3.1819-3.6420.19381450.1452151699
3.642-4.58730.14091480.12541564100
4.5873-38.1550.18151560.1563164699
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.1878-1.3925-0.93953.62980.28712.7681-0.0804-0.09550.14390.07610.052-0.2102-0.1130.3929-0.01550.1361-0.0313-0.01920.17140.01530.0852-11.5405-17.3235-4.5913
22.3125-0.03510.00230.5632-0.10581.9999-0.0610.26510.0903-0.02920.0182-0.0932-0.00740.30560.03010.1112-0.0114-0.00190.14440.00980.0969-8.521-20.34921.6534
34.3465-0.9279-0.40471.11940.19251.4385-0.00810.0697-0.047-0.01660.0117-0.01730.02510.0101-0.0080.0905-0.0144-0.00240.04910.00020.0614-19.2704-22.93816.4499
43.6861-0.9614-4.95780.78541.01946.80920.41220.08080.3737-0.2011-0.0687-0.1474-0.7241-0.0562-0.31330.1655-0.00420.01410.14160.00640.1497-3.6761-10.501719.0289
52.27290.1052-0.18160.98590.09060.9307-0.0233-0.13950.04980.08740.0258-0.03610.00010.0605-0.00360.09770-0.01410.05040.00230.0719-12.9658-17.884231.2193
65.75275.0046-1.18764.6135-1.84422.84440.2016-0.20760.16080.1667-0.13240.19140.0047-0.1511-0.06810.1726-0.00150.00470.056-0.02420.1049-20.7017-34.374127.0776
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 389 through 421 )A389 - 421
2X-RAY DIFFRACTION2chain 'A' and (resid 422 through 481 )A422 - 481
3X-RAY DIFFRACTION3chain 'A' and (resid 482 through 541 )A482 - 541
4X-RAY DIFFRACTION4chain 'A' and (resid 542 through 565 )A542 - 565
5X-RAY DIFFRACTION5chain 'A' and (resid 566 through 643 )A566 - 643
6X-RAY DIFFRACTION6chain 'A' and (resid 644 through 658 )A644 - 658

+
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