[English] 日本語
Yorodumi
- PDB-6xvb: Crystal structure of the kinase domain of human c-KIT with a cycl... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6xvb
TitleCrystal structure of the kinase domain of human c-KIT with a cyclic imidate inhibitor covalently bound to Cys788
ComponentsMast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
KeywordsSIGNALING PROTEIN / type II kinase inhibitor / structure-based drug design / covalent inhibitor / cysteine reactive warhead
Function / homology
Function and homology information


Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants ...Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants / Signaling by extracellular domain mutants of KIT / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / melanocyte migration / stem cell factor receptor activity / mast cell proliferation / positive regulation of vascular associated smooth muscle cell differentiation / Kit signaling pathway / positive regulation of dendritic cell cytokine production / tongue development / positive regulation of small intestine smooth muscle contraction / positive regulation of mast cell cytokine production / mast cell differentiation / mast cell chemotaxis / Fc receptor signaling pathway / immature B cell differentiation / epithelial cell proliferation / melanocyte differentiation / positive regulation of long-term neuronal synaptic plasticity / primordial germ cell migration / positive regulation of pseudopodium assembly / detection of mechanical stimulus involved in sensory perception of sound / megakaryocyte development / erythropoietin-mediated signaling pathway / somatic stem cell population maintenance / pigmentation / embryonic hemopoiesis / digestive tract development / lamellipodium assembly / Regulation of KIT signaling / stem cell population maintenance / positive regulation of Notch signaling pathway / growth factor binding / positive regulation of tyrosine phosphorylation of STAT protein / Developmental Lineage of Mammary Gland Alveolar Cells / ovarian follicle development / hemopoiesis / cytokine binding / hematopoietic progenitor cell differentiation / T cell differentiation / Developmental Lineage of Mammary Gland Luminal Epithelial Cells / response to cadmium ion / B cell differentiation / stem cell differentiation / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / male gonad development / Transcriptional and post-translational regulation of MITF-M expression and activity / visual learning / acrosomal vesicle / SH2 domain binding / erythrocyte differentiation / positive regulation of receptor signaling pathway via JAK-STAT / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / mast cell degranulation / cell chemotaxis / Signaling by SCF-KIT / receptor protein-tyrosine kinase / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cytoplasmic side of plasma membrane / regulation of cell shape / cell-cell junction / actin cytoskeleton organization / PIP3 activates AKT signaling / regulation of cell population proliferation / protein autophosphorylation / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protease binding / protein tyrosine kinase activity / spermatogenesis / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / signaling receptor complex / positive regulation of cell migration / inflammatory response / external side of plasma membrane / positive regulation of cell population proliferation / signal transduction / protein homodimerization activity / : / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
Mast/stem cell growth factor receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain ...Mast/stem cell growth factor receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-O2H / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsSchimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. ...Schimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Kettle, J.G. / Waring, M.J.
CitationJournal: J.Am.Chem.Soc. / Year: 2020
Title: Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.
Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / ...Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Waring, M.J. / Kettle, J.G.
History
DepositionJan 21, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2May 1, 2024Group: 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
Revision 1.3Oct 23, 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: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
B: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,7464
Polymers74,6652
Non-polymers1,0812
Water1,69394
1
A: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8732
Polymers37,3331
Non-polymers5411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8732
Polymers37,3331
Non-polymers5411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.710, 90.272, 91.178
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

-
Components

#1: Protein Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit / SCFR / Piebald trait protein / PBT / Proto-oncogene c-Kit / Tyrosine-protein kinase Kit / p145 c- ...SCFR / Piebald trait protein / PBT / Proto-oncogene c-Kit / Tyrosine-protein kinase Kit / p145 c-kit / v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog


Mass: 37332.578 Da / Num. of mol.: 2
Fragment: protein kinase domain (551-934 del[688-755]),protein kinase domain (551-934 del[688-755])
Mutation: I563S,V569S,Y609Q,L631S,M651E,I662H,D768H,R804N,V825D,C844S,L890S,H894Y,L912D,L923D
Source method: isolated from a genetically manipulated source
Details: co-expression with PTPN1 (P18031-1) / Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Plasmid: pET28b / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): BL21 Star (DE3)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-O2H / ~{N}-(4,4-dimethyl-2-propyl-3,1-benzoxazin-6-yl)-2-[3-methoxy-5-(7-methoxyquinolin-4-yl)oxy-pyridin-2-yl]ethanamide


Mass: 540.610 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H32N4O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.42 Å3/Da / Density % sol: 49.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.2
Details: 9 % PEG8000, 18 % ethylene glycol, 10 % MORPHEUS halogens, 0.1 M Imidazole-MES buffer pH 6.2

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97623 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jun 28, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97623 Å / Relative weight: 1
ReflectionResolution: 2.15→63.211 Å / Num. obs: 35714 / % possible obs: 92.7 % / Redundancy: 6.7 % / Biso Wilson estimate: 55.24 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.096 / Net I/σ(I): 9.9
Reflection shellResolution: 2.15→2.251 Å / Redundancy: 1.4 % / Num. unique obs: 1783 / CC1/2: 0.509 / % possible all: 47.7

-
Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 2.15→63.21 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.94 / SU R Cruickshank DPI: 0.23 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.228 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.182
RfactorNum. reflection% reflectionSelection details
Rfree0.223 1950 5.46 %RANDOM
Rwork0.192 ---
obs0.194 35714 89.3 %-
Displacement parametersBiso max: 160.5 Å2 / Biso mean: 66.71 Å2 / Biso min: 29.98 Å2
Baniso -1Baniso -2Baniso -3
1--3.3493 Å20 Å20 Å2
2--2.4448 Å20 Å2
3---0.9045 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 2.15→63.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4629 0 80 94 4803
Biso mean--60.77 56.98 -
Num. residues----585
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1659SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes800HARMONIC5
X-RAY DIFFRACTIONt_it4835HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion605SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5507SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4835HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6549HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion17.65
LS refinement shellResolution: 2.15→2.21 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2683 48 6.71 %
Rwork0.216 667 -
all0.2194 715 -
obs--23.54 %
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)
11.5715-0.14750.65651.631-0.62923.748-0.0443-0.00260.05660.0229-0.0207-0.0192-0.0753-0.0140.0649-0.24120.06270.0272-0.1609-0.0105-0.1721-16.882537.951729.602
21.81211.048-0.17116.1808-0.05651.34420.01130.0272-0.35410.1149-0.0078-0.03620.25790.0971-0.0036-0.24620.0551-0.0072-0.17330.0046-0.139619.603444.644125.0523
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A569 - 931
2X-RAY DIFFRACTION2{ B|* }B577 - 931

+
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