[English] 日本語
Yorodumi
- PDB-4cnh: Structure of the Human Anaplastic Lymphoma Kinase in Complex with... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4cnh
TitleStructure of the Human Anaplastic Lymphoma Kinase in Complex with the inhibitor 3-((1R)-1-(5-fluoro-2-methoxyphenyl)ethoxy)-5-(1-methyl-1H- 1,2,3-triazol-5-yl)pyridin-2-amine
ComponentsALK TYROSINE KINASE RECEPTOR
KeywordsTRANSFERASE / RECEPTOR TYROSINE KINASE / INHIBITOR
Function / homology
Function and homology information


ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / MDK and PTN in ALK signaling / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway ...ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / MDK and PTN in ALK signaling / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway / response to environmental enrichment / ALK mutants bind TKIs / swimming behavior / positive regulation of dendrite development / regulation of neuron differentiation / adult behavior / Signaling by ALK / neuron development / negative regulation of lipid catabolic process / energy homeostasis / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / hippocampus development / cell surface receptor protein tyrosine kinase signaling pathway / Signaling by ALK fusions and activated point mutants / receptor protein-tyrosine kinase / heparin binding / positive regulation of NF-kappaB transcription factor activity / regulation of cell population proliferation / regulation of apoptotic process / protein tyrosine kinase activity / protein autophosphorylation / receptor complex / phosphorylation / signal transduction / protein-containing complex / extracellular exosome / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
Glycine rich protein / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Tyrosine-protein kinase, catalytic domain ...Glycine rich protein / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Concanavalin A-like lectin/glucanase domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-3U9 / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsMcTigue, M.A. / Deng, Y.L. / Liu, W. / Brooun, A. / Stewart, A.E.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile (Pf-06463922), a ...Title: Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile (Pf-06463922), a Macrocyclic Inhibitor of Alk/Ros1 with Pre-Clinical Brain Exposure and Broad Spectrum Potency Against Alk-Resistant Mutations.
Authors: Johnson, T.W. / Richardson, P.F. / Bailey, S. / Brooun, A. / Burke, B.J. / Collins, M.R. / Cui, J.J. / Deal, J.G. / Deng, Y.L. / Dinh, D.M. / Engstrom, L.D. / He, M. / Hoffman, J.E. / ...Authors: Johnson, T.W. / Richardson, P.F. / Bailey, S. / Brooun, A. / Burke, B.J. / Collins, M.R. / Cui, J.J. / Deal, J.G. / Deng, Y.L. / Dinh, D.M. / Engstrom, L.D. / He, M. / Hoffman, J.E. / Hoffman, R.L. / Huang, Q. / Kath, J. / Kania, R.S. / Lam, H. / Lam, J.L. / Le, P.T. / Lingardo, L. / Liu, W. / Mctigue, M.A. / Palmer, C.L. / Sach, N.W. / Smeal, T. / Smith, G.L. / Stewart, A.E. / Timofeevski, S.L. / Zhu, H. / Zhu, J. / Zou, H.Y. / Edwards, M.P.
History
DepositionJan 22, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 28, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 25, 2014Group: Database references / Other / Refinement description
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / 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 / software / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _software.name / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: ALK TYROSINE KINASE RECEPTOR
B: ALK TYROSINE KINASE RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,8495
Polymers73,8192
Non-polymers1,0303
Water5,693316
1
A: ALK TYROSINE KINASE RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2532
Polymers36,9091
Non-polymers3431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: ALK TYROSINE KINASE RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5963
Polymers36,9091
Non-polymers6872
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.613, 103.652, 57.779
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number4
Space group name H-MP1211

-
Components

#1: Protein ALK TYROSINE KINASE RECEPTOR / ANAPLASTIC LYMPHOMA KINASE / ANAPLASTIC LYMPHOMA KINASE


Mass: 36909.355 Da / Num. of mol.: 2 / Fragment: TYROSINE KINASE DOMAIN, RESIDUES 1093-1411
Source method: isolated from a genetically manipulated source
Details: NONPHOSPHORYLATED / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-3U9 / 3-[(1R)-1-(5-fluoro-2-methoxyphenyl)ethoxy]-5-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-amine


Mass: 343.356 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C17H18FN5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 316 / 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: 2.1 Å3/Da / Density % sol: 41 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION (APPROXIMATELY 13-15 MG/ML)CONTAINING 0.001M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION ...Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION (APPROXIMATELY 13-15 MG/ML)CONTAINING 0.001M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION CONTAINING: 0.15M AMMONIUM SULFATE, 9-10.5% MONOMETHYLETHER PEG5K AND 0.1M MES IN THE PH RANGE 5.3-6.5.

-
Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorDetector: CCD / Date: Feb 10, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.84→103.65 Å / Num. obs: 48479 / % possible obs: 92 % / Observed criterion σ(I): 1 / Redundancy: 3.4 % / Biso Wilson estimate: 13.4 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 9.6
Reflection shellResolution: 1.84→1.94 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 2.1 / % possible all: 81.5

-
Processing

Software
NameVersionClassification
CNX2005refinement
autoPROCdata reduction
SCALAdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2XP2

2xp2


Resolution: 1.9→36.57 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 140646.51 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.25 3931 4.9 %RANDOM
Rwork0.203 ---
obs0.206 80358 85.2 %-
all-88428 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.9846 Å2 / ksol: 0.384999 e/Å3
Displacement parametersBiso mean: 29 Å2
Baniso -1Baniso -2Baniso -3
1--7.57 Å20 Å20 Å2
2--10.13 Å20 Å2
3----2.57 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.4 Å0.35 Å
Refinement stepCycle: LAST / Resolution: 1.9→36.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4580 0 75 316 4971
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
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_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.411.5
X-RAY DIFFRACTIONc_mcangle_it2.192
X-RAY DIFFRACTIONc_scbond_it2.372
X-RAY DIFFRACTIONc_scangle_it3.472.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.9→2.02 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.388 574 4.9 %
Rwork0.351 11056 -
obs--74.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARAMDNA-RNA.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5UNL.PARAMUNL.TOP

+
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