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- PDB-9gbe: Structure of Human Anaplastic Lymphoma Kinase (ALK) harboring the... -

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Basic information

Entry
Database: PDB / ID: 9gbe
TitleStructure of Human Anaplastic Lymphoma Kinase (ALK) harboring the G1202R/L1196M Compound Mutation in Complex with NVL-655
ComponentsALK tyrosine kinase receptor
KeywordsONCOPROTEIN / ALK / Tyrosine Kinase Inhibitor / Resistance / NVL-655
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 / Signaling by ALK / adult behavior / neuron development / negative regulation of lipid catabolic process / phosphorylation / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / heparin binding / positive regulation of NF-kappaB transcription factor activity / regulation of cell population proliferation / protein tyrosine kinase activity / regulation of apoptotic process / protein autophosphorylation / receptor complex / 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. / : ...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. / Tyrosine-protein kinase, active site / Concanavalin A-like lectin/glucanase 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
: / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.58 Å
AuthorsMente, S. / Horan, J.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cancer Discov / Year: 2024
Title: NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations.
Authors: Lin, J.J. / Horan, J.C. / Tangpeerachaikul, A. / Swalduz, A. / Valdivia, A. / Johnson, M.L. / Besse, B. / Camidge, D.R. / Fujino, T. / Yoda, S. / Nguyen-Phuong, L. / Mizuta, H. / Bigot, L. / ...Authors: Lin, J.J. / Horan, J.C. / Tangpeerachaikul, A. / Swalduz, A. / Valdivia, A. / Johnson, M.L. / Besse, B. / Camidge, D.R. / Fujino, T. / Yoda, S. / Nguyen-Phuong, L. / Mizuta, H. / Bigot, L. / Nobre, C. / Lee, J.B. / Yu, M.R. / Mente, S. / Sun, Y. / Kohl, N.E. / Porter, J.R. / Shair, M.D. / Zhu, V.W. / Felip, E. / Cho, B.C. / Friboulet, L. / Hata, A.N. / Pelish, H.E. / Drilon, A.
History
DepositionJul 31, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 18, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3862
Polymers38,9331
Non-polymers4531
Water3,801211
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.525, 57.198, 105.229
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein ALK tyrosine kinase receptor / Anaplastic lymphoma kinase


Mass: 38932.777 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1IJ8 / NVL-655 / (14R)-5-Chloro-7-ethyl-16-fluoro-2,14-dihydro-2,14-dimethyl-7H-8,12-metheno-4H-dipyrazolo[3,4-h:4',3'-k][2,5]benzoxaazacyclotetradecin-11-amine / 7H-8,12-Metheno-4H-dipyrazolo[3,4-h:4',3'-k][2,5]benzoxaazacyclotetradecin- 11-amine, 5-chloro-7-ethyl-16-fluoro-2,14-dihydro- 2,14-dimethyl-, (14R)-


Mass: 452.912 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22ClFN6O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

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

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Sample preparation

CrystalDensity Matthews: 1.99 Å3/Da / Density % sol: 38.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 16-22% (w/v) PEG3350 pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.578→52.615 Å / Num. obs: 43503 / % possible obs: 99.9 % / Redundancy: 7.3 % / CC1/2: 0.999 / Net I/σ(I): 14.6
Reflection shellResolution: 1.578→1.606 Å / Num. unique obs: 14849 / CC1/2: 0.751

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.28data extraction
autoPROCdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.58→52.61 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.953 / SU B: 6.212 / SU ML: 0.097 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.092 / ESU R Free: 0.096 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2236 3937 9.1 %RANDOM
Rwork0.1827 ---
obs0.1863 39564 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 135.53 Å2 / Biso mean: 40.695 Å2 / Biso min: 17.92 Å2
Baniso -1Baniso -2Baniso -3
1--0.89 Å2-0 Å2-0 Å2
2---3.83 Å20 Å2
3---4.71 Å2
Refinement stepCycle: final / Resolution: 1.58→52.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2401 0 32 211 2644
Biso mean--34 46.28 -
Num. residues----304
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0132608
X-RAY DIFFRACTIONr_bond_other_d0.0020.0172441
X-RAY DIFFRACTIONr_angle_refined_deg1.4551.6653573
X-RAY DIFFRACTIONr_angle_other_deg1.31.5785631
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3065336
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.99221.76125
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.51915426
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7881517
X-RAY DIFFRACTIONr_chiral_restr0.0780.2344
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023015
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02592
X-RAY DIFFRACTIONr_mcbond_it2.422.5251302
X-RAY DIFFRACTIONr_mcbond_other2.4112.5241301
X-RAY DIFFRACTIONr_mcangle_it3.6294.2121652
LS refinement shellResolution: 1.58→1.619 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.347 283 -
Rwork0.376 2878 -
obs--99.87 %
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)
11.2027-0.40130.09252.7111.41433.7047-0.0522-0.2129-0.02410.20180.0119-0.0348-0.21430.00840.04040.19930.04260.0230.26730.04710.0512-20.68923.347-8.689
22.5526-0.68180.15893.2187-0.21911.41180.0282-0.0785-0.05820.16580.04290.15510.00870.0613-0.0710.08660.00080.01090.21170.01380.0114-9.8833.48-21.117
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1086 - 1401
2X-RAY DIFFRACTION2A1501

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