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- PDB-8pqf: c-KIT kinase domain in complex with avapritinib derivative 12 -

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Basic information

Entry
Database: PDB / ID: 8pqf
Titlec-KIT kinase domain in complex with avapritinib derivative 12
ComponentsMast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE / c-KIT protein kinase / avapritinib / inhibitor / tyrosine kinase / transmembrane receptor / stem cell factor / SCF / stem cell factor receptor / GIST / gastrointestinal stromal tumors / P10721
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 / stem cell factor receptor activity / hematopoietic stem cell migration / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / erythropoietin-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / positive regulation of dendritic cell cytokine production / Kit signaling pathway / regulation of bile acid metabolic process / positive regulation of small intestine smooth muscle contraction / mast cell differentiation / positive regulation of mast cell proliferation / mast cell chemotaxis / Fc receptor signaling pathway / glycosphingolipid metabolic process / mast cell proliferation / positive regulation of long-term neuronal synaptic plasticity / detection of mechanical stimulus involved in sensory perception of sound / positive regulation of pseudopodium assembly / immature B cell differentiation / melanocyte differentiation / positive regulation of mast cell cytokine production / lymphoid progenitor cell differentiation / germ cell migration / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / tongue development / megakaryocyte development / Regulation of KIT signaling / pigmentation / stem cell population maintenance / mast cell degranulation / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / growth factor binding / somatic stem cell population maintenance / hemopoiesis / T cell differentiation / spermatid development / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / : / response to cadmium ion / ovarian follicle development / positive regulation of tyrosine phosphorylation of STAT protein / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SH2 domain binding / B cell differentiation / erythrocyte differentiation / cell chemotaxis / acrosomal vesicle / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / epithelial cell proliferation / stem cell differentiation / positive regulation of receptor signaling pathway via JAK-STAT / visual learning / Signaling by SCF-KIT / receptor protein-tyrosine kinase / cytoplasmic side of plasma membrane / fibrillar center / cytokine-mediated signaling pathway / positive regulation of DNA-binding transcription factor activity / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / cell-cell junction / PIP3 activates AKT signaling / regulation of cell population proliferation / regulation of cell shape / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / actin cytoskeleton organization / RAF/MAP kinase cascade / spermatogenesis / protein tyrosine kinase activity / protease binding / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / intracellular signal transduction / positive regulation of cell migration / inflammatory response
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 / Tyrosine protein kinases specific active-site signature. ...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-9KI / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsTeuber, A. / Mueller, M.P. / Rauh, D.
Funding supportEuropean Union, Germany, 4items
OrganizationGrant numberCountry
European Regional Development FundEFRE-800400European Union
German Federal Ministry for Education and Research01ZX2201B Germany
Other privateEx-2021-0033
Other governmentNW21-062C
CitationJournal: Nat Commun / Year: 2024
Title: Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA.
Authors: Teuber, A. / Schulz, T. / Fletcher, B.S. / Gontla, R. / Muhlenberg, T. / Zischinsky, M.L. / Niggenaber, J. / Weisner, J. / Kleinbolting, S.B. / Lategahn, J. / Sievers, S. / Muller, M.P. / Bauer, S. / Rauh, D.
History
DepositionJul 11, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 27, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 13, 2024Group: Database references / Category: pdbx_related_exp_data_set

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mast/stem cell growth factor receptor Kit
C: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,5024
Polymers74,3892
Non-polymers1,1132
Water5,116284
1
A: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7512
Polymers37,1941
Non-polymers5571
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7512
Polymers37,1941
Non-polymers5571
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.090, 59.250, 191.830
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein 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: 37194.430 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-9KI / methyl ~{N}-[(1~{S})-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethyl]carbamate


Mass: 556.594 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H29FN10O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 284 / 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: 1.9 Å3/Da / Density % sol: 35.35 %
Crystal growTemperature: 285.15 K / Method: vapor diffusion, hanging drop / Details: 3 mg/mL, 21% PEG3350, 125 mM Li3-citrate

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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 EIGER2 X 16M / Detector: PIXEL / Date: Feb 10, 2023
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→47.96 Å / Num. obs: 53195 / % possible obs: 100 % / Redundancy: 13.36 % / Biso Wilson estimate: 40.35 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.094 / Net I/σ(I): 14.58
Reflection shellResolution: 1.9→2 Å / Redundancy: 12.86 % / Mean I/σ(I) obs: 1.53 / Num. unique obs: 7488 / CC1/2: 0.738 / Rrim(I) all: 1.597 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→43 Å / SU ML: 0.2274 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.2202
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2186 2659 5 %
Rwork0.1957 50517 -
obs0.1968 53176 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 47.66 Å2
Refinement stepCycle: LAST / Resolution: 1.9→43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4614 0 82 284 4980
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034888
X-RAY DIFFRACTIONf_angle_d0.63356659
X-RAY DIFFRACTIONf_chiral_restr0.0416719
X-RAY DIFFRACTIONf_plane_restr0.0046845
X-RAY DIFFRACTIONf_dihedral_angle_d14.10441754
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.930.34121390.34472653X-RAY DIFFRACTION100
1.93-1.970.34681380.3052604X-RAY DIFFRACTION100
1.97-2.010.31281370.28082607X-RAY DIFFRACTION100
2.01-2.060.31241370.25842608X-RAY DIFFRACTION99.93
2.06-2.10.27991390.2442631X-RAY DIFFRACTION100
2.1-2.160.22791380.21632635X-RAY DIFFRACTION100
2.16-2.210.26911380.21632608X-RAY DIFFRACTION99.93
2.21-2.280.24121400.21192656X-RAY DIFFRACTION99.93
2.28-2.350.23051370.21322616X-RAY DIFFRACTION99.85
2.35-2.440.24021390.21212634X-RAY DIFFRACTION99.96
2.44-2.530.29431390.21542637X-RAY DIFFRACTION99.96
2.54-2.650.22751400.22712652X-RAY DIFFRACTION99.96
2.65-2.790.24851390.23272658X-RAY DIFFRACTION100
2.79-2.960.21761410.22982664X-RAY DIFFRACTION100
2.96-3.190.24741400.22372660X-RAY DIFFRACTION99.96
3.19-3.510.25371410.19662675X-RAY DIFFRACTION100
3.51-4.020.18031420.15992703X-RAY DIFFRACTION100
4.02-5.070.15871440.14452737X-RAY DIFFRACTION99.97
5.07-430.1941510.18182879X-RAY DIFFRACTION99.84
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)
10.4038886210790.1546708995470.4475561866670.134633651268-0.4512696238781.64417686909-0.0197602210595-0.001535577242280.0219009622955-0.0847279344218-0.01405771743260.0704249689443-0.29685315482-0.270381143983-8.67904890319E-60.3988023355810.02836001854940.02787923928940.396714765955-0.01984868210830.410646055368-9.133331686274.7517587089-3.11161215483
21.36983740176-0.3546471497520.1825682534531.719861244010.5350686242212.069070446550.0654081326149-0.0245982608766-0.05052631857960.0110742750683-0.04856496709360.04007002345260.0250095815632-0.1803340706975.87151498852E-60.3413651413680.009005806072040.01423696971750.363982424212-0.02244309105260.376471055468-5.37076384267-1.7862228836511.7969139601
30.9818340120270.06268705666-0.7493852808241.168601467040.5253276289571.72752064908-0.139280408157-0.174005916149-0.1497471876350.0649299130881-0.05479669336610.0765860707914-0.00608149284323-0.0462383118044-6.46722073595E-50.419366157130.0405861833017-0.001278909753630.378449237737-0.01244371066020.381510074975-12.3050014161-20.572666861.8746014389
41.48682923931-0.4572036429390.03760206046452.086656751370.8352786452272.72976386585-0.0306729472239-0.02844324767040.0314487014067-0.151693325971-0.1520786761610.103908724816-0.431136440144-0.133327804632-0.0008170546717570.3876523300190.0588980927505-0.03218393121090.347324693787-0.04003739378290.355111729664-15.5591030805-26.466158578137.857162837
50.8392760184520.8468853274720.1255334641270.809554484715-0.09413037462651.42208315109-0.06112893778750.180010503738-0.0685355240223-0.2953780815480.0557111619444-0.108991168767-0.113742037917-0.126010932045-5.75881150802E-60.367366313178-0.004000643281780.02136770274460.3968012425850.0008075597350550.384742841927-11.2553511257-0.983305150248-14.467677883
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'C' and (resid 631 through 765 )CC631 - 76566 - 132
22chain 'C' and (resid 766 through 932 )CC766 - 932133 - 297
33chain 'A' and (resid 566 through 677 )AA566 - 6771 - 111
44chain 'A' and (resid 678 through 931 )AA678 - 931112 - 294
55chain 'C' and (resid 566 through 630 )CC566 - 6301 - 65

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