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- PDB-7nx4: Crystal structure of the TG and EGF-like domains of ALK -

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Basic information

Entry
Database: PDB / ID: 7nx4
TitleCrystal structure of the TG and EGF-like domains of ALK
ComponentsALK tyrosine kinase receptor
KeywordsPROTEIN BINDING / Cell Surface Receptor Cytokine binding
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 / cell surface receptor protein tyrosine kinase signaling pathway / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / positive regulation of NF-kappaB transcription factor activity / heparin binding / 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 / 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
NICKEL (II) ION / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsDe Munck, S. / Savvides, S.N.
Funding support Belgium, 1items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO) Belgium
CitationJournal: Nature / Year: 2021
Title: Structural basis of cytokine-mediated activation of ALK family receptors.
Authors: De Munck, S. / Provost, M. / Kurikawa, M. / Omori, I. / Mukohyama, J. / Felix, J. / Bloch, Y. / Abdel-Wahab, O. / Bazan, J.F. / Yoshimi, A. / Savvides, S.N.
History
DepositionMar 17, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 27, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 15, 2021Group: 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 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,5678
Polymers40,5001
Non-polymers1,0687
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1180 Å2
ΔGint-28 kcal/mol
Surface area16490 Å2
Unit cell
Length a, b, c (Å)84.930, 84.930, 148.666
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number80
Space group name H-MI41
Space group name HallI4bw
Symmetry operation#1: x,y,z
#2: -y+1/2,x,z+3/4
#3: y+1/2,-x,z+3/4
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: -y+1,x+1/2,z+5/4
#7: y+1,-x+1/2,z+5/4
#8: -x+1/2,-y+1/2,z+1/2

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Components

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


Mass: 40499.660 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Production host: Homo sapiens (human)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ni
Has ligand of interestN

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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: 3.31 Å3/Da / Density % sol: 62.84 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop
Details: to 0.5mM Manganese(II) chloride tetrahydrate, 0.5mM Cobalt(II) chloride hexahydrate, 0.5mM Nickel(II) chloride hexahydrate, 0.5mM Zinc acetate dihydrate, 13% w/v PEG 3000, 28% v/v 1,2,4- ...Details: to 0.5mM Manganese(II) chloride tetrahydrate, 0.5mM Cobalt(II) chloride hexahydrate, 0.5mM Nickel(II) chloride hexahydrate, 0.5mM Zinc acetate dihydrate, 13% w/v PEG 3000, 28% v/v 1,2,4- Butanetriol, 1% w/v NDSB 256

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 3→60.05 Å / Num. obs: 10550 / % possible obs: 99.9 % / Redundancy: 14.3 % / Biso Wilson estimate: 104.34 Å2 / CC1/2: 1 / Rrim(I) all: 0.189 / Net I/σ(I): 10.15
Reflection shellResolution: 3→3.18 Å / Num. unique obs: 1714 / Rrim(I) all: 1.15

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHENIX1.17.1_3660refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7NX3

7nx3


Resolution: 3→60.05 Å / SU ML: 0.5604 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.6326
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2471 528 5.01 %
Rwork0.2191 10021 -
obs0.2205 10549 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 103.25 Å2
Refinement stepCycle: LAST / Resolution: 3→60.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2496 0 59 0 2555
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00222608
X-RAY DIFFRACTIONf_angle_d0.52843534
X-RAY DIFFRACTIONf_chiral_restr0.0447377
X-RAY DIFFRACTIONf_plane_restr0.0027474
X-RAY DIFFRACTIONf_dihedral_angle_d10.3779386
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.30.39731310.39752497X-RAY DIFFRACTION99.77
3.3-3.780.29761320.28782495X-RAY DIFFRACTION99.85
3.78-4.760.24521320.20152507X-RAY DIFFRACTION100
4.76-60.050.20521330.18132522X-RAY DIFFRACTION99.81
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)
11.185171879180.676597984637-0.827012887281.29812802785-0.1383064874390.7730914063920.405021471396-0.182864966387-0.03176762094830.924849332804-0.667833937147-0.178897613854-0.2556029186020.4447178483540.0009197853628930.983802960531-0.01097611662860.1224154848921.045390849780.09506297513290.82922729899942.055152976126.8157206999-10.1496766791
22.37987437995-0.353196189642-2.659657303583.551603577350.6802024376752.768026783850.1883181257690.621966095589-0.4673398209220.105778110436-0.0548204069252-0.03767337166410.5470097820720.659867856998-0.0007440607818290.899833036842-0.0157487087547-0.06194130993980.9898696149510.03689637917610.66640041740.595570491623.725851187-15.7888537948
32.06684873941-0.577135487370.2008483461930.746873911394-1.216168102072.121475396680.0101370869744-0.169998771208-0.0216022159099-0.112396597390.402694986480.3581042770360.280963252327-0.3286713577480.0009355769167890.994852204399-0.07002215712480.08286022871630.9432850463810.1376799311440.82262840152834.366784761519.5668984603-4.02236340651
40.1362994011410.2002657619190.136652732410.459002434334-0.07937766372090.2038901103430.136646214909-1.40221581231-0.2835056507934.437227496380.27326941701-2.458420898020.8028952995190.2169375599910.0013517946181.30652887636-0.1491684857830.06183128965881.80891143430.04398481893391.4145773546428.543693558935.78490007685.53654821137
51.045007279920.0633607270057-0.6132486665841.92985833907-1.83460409711.957982943750.169538001662-0.1466000578640.2317192345890.270287266102-0.1271186878630.213436478491-0.0564070342487-0.2354254101670.0004078638842930.7899980097060.01702534332320.02186752260191.12140722741-0.005748759305660.86491787340533.423744572934.0666136545-6.2583649033
60.06503709699680.0865285277505-0.1608236189460.8690589093550.05768563677730.467327404975-0.353109800889-0.9935240287491.684822765341.169417931270.689553575733-0.0677143045012-0.842892830807-0.319691326570.001021577720221.360341919130.3836157009110.1431097835951.23725411186-0.2388130015771.7474215694119.996044210860.47212802724.07558757806
72.94029390418-1.17015097568-0.09311011635152.80873403198-1.42345297850.849865243093-0.0222535979079-0.2271794902630.2728548017390.413326949190.5438268358760.1949980057840.142466629115-0.4610382619349.92838302041E-60.727367902595-0.02172929348990.1472604369241.098857553750.1068005721260.9142005202923.873444719533.2835696392-7.01678277908
80.01676324387640.0569445203603-0.04015299854840.1477477166860.1071716129260.06264275617490.536268580933-1.58967297507-0.01830106672151.67334361257-1.474971769750.03350791266340.899321189462-0.633080143579-0.001745809788381.676044073760.06093051448810.4328659309341.62313117549-0.2269401037741.586176058519.300401440532.59911737817.47204119647
92.12075504847-1.537167366471.475094484511.67786566745-0.5774555499651.7865063242-0.198514986424-0.1229252908580.04860352477180.3823563524570.1587974066170.9473294188780.0975967533968-1.14903108952-0.000195436888920.658613484556-0.04858327011110.06008670435651.330684760890.06304547570581.135726387319.057174633433.4849256234-12.2171227784
101.994778886623.856307459812.062808615118.760796072976.72024495287.83281280429-1.915788171360.3019471421591.6882922688-0.9530792035130.233918384535-0.428233237024-0.464454579012-0.287600735194-0.6183656484060.4115357492010.0506461282885-0.04484841503141.614965248560.08500275855360.78730572897124.052473041556.3636754182-9.58935460165
111.04375111267-0.7725901104320.1966063763331.07688284075-0.5092907833160.4269708645510.135596786449-0.1920222247310.2151743649290.749446119808-0.07676787618861.18940357827-0.213077694413-0.499878847524-9.3260212125E-50.8309992063630.04368274180910.2295522039661.327380766270.04646444417711.1098366333820.947710194137.5673234125-3.96856150461
120.914642876968-0.5158724594920.1633995491060.865698357853-0.5711665247650.2870820249750.00536272959386-0.670450382224-0.1391120503361.085091601760.587864102586-0.419746702666-0.6680378496230.121766675316-0.001722212998161.56273928551-0.1808836816310.1652888975391.435769802350.156937540221.2735718900827.631719106319.2411117453.21995940446
132.171555775370.8626984404010.6580247167540.6578246469860.3170866161250.2029902418060.470527960712-1.015872916330.42099890551.47577657718-0.156824461930.8728812514270.2966877087321.71538491757-0.01915391045911.363604841860.1445337173620.1801482483161.164893919810.01931953179960.66683705801837.49383305316.3777739839-0.193121160859
140.413473695012-0.149554769264-0.1323481787870.0784730173010.1614855085570.231996247716-0.48391300303-0.102690291744-0.0208401823015-0.3004600178690.8212062874780.6286039074570.559205665085-0.775381011881-0.001514506079591.42591864878-0.02926881948240.007013277997010.9278511124490.03589908762050.78151201345539.775758433310.567066831311.3301764023
151.70677630195-0.849566160590.2711915508170.4709628199570.1027415500610.5909125466220.1915857129320.03504244126440.93430854316-0.8903984172390.000707497228415-1.19115742417-1.91717970941-0.156872186574-0.001057512597181.30183843244-0.2262263331470.06290486641511.066582817590.04134510483581.088237940347.98272812296.486690946645.40947495222
160.605202415253-0.2787185005420.02273491296780.641700309690.256033082010.022087824335-1.07611676661-2.03991961460.956098252754-0.3967312371440.158751293249-0.3781814545560.0473715977856-0.750199443739-0.01028497888021.0817924818-0.07266629300190.1263155466580.854674132248-0.1982852773911.1290156142249.92208177512.160251535418.5942461632
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 679:704)
2X-RAY DIFFRACTION2(chain A and resid 705:727)
3X-RAY DIFFRACTION3(chain A and resid 728:746)
4X-RAY DIFFRACTION4(chain A and resid 747:760)
5X-RAY DIFFRACTION5(chain A and resid 761:796)
6X-RAY DIFFRACTION6(chain A and resid 797:808)
7X-RAY DIFFRACTION7(chain A and resid 809:850)
8X-RAY DIFFRACTION8(chain A and resid 851:861)
9X-RAY DIFFRACTION9(chain A and resid 862:909)
10X-RAY DIFFRACTION10(chain A and resid 910:913)
11X-RAY DIFFRACTION11(chain A and resid 914:960)
12X-RAY DIFFRACTION12(chain A and resid 961:974)
13X-RAY DIFFRACTION13(chain A and resid 975:987)
14X-RAY DIFFRACTION14(chain A and resid 988:995)
15X-RAY DIFFRACTION15(chain A and resid 996:1010)
16X-RAY DIFFRACTION16(chain A and resid 1011:1025)

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