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- PDB-7uks: Crystal structure of SOS1 with phthalazine inhibitor bound (compo... -

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Basic information

Entry
Database: PDB / ID: 7uks
TitleCrystal structure of SOS1 with phthalazine inhibitor bound (compound 15)
ComponentsSon of sevenless homolog 1
KeywordsSIGNALING PROTEIN/INHIBITOR / SOS1 / KRAS / RAS / protein-protein interaction / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling ...midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling / Activation of RAC1 / blood vessel morphogenesis / positive regulation of epidermal growth factor receptor signaling pathway / Regulation of KIT signaling / epidermal growth factor receptor binding / leukocyte migration / regulation of T cell proliferation / NRAGE signals death through JNK / roof of mouth development / eyelid development in camera-type eye / Fc-epsilon receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / neurotrophin TRK receptor signaling pathway / SOS-mediated signalling / RET signaling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / hair follicle development / SHC1 events in ERBB4 signaling / Signalling to RAS / fibroblast growth factor receptor signaling pathway / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / Signal attenuation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Schwann cell development / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / RAC1 GTPase cycle / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / myelination / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / Insulin receptor signalling cascade / GTPase activator activity / guanyl-nucleotide exchange factor activity / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / molecular condensate scaffold activity / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / response to ischemia / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / axon guidance / B cell receptor signaling pathway / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / multicellular organism growth / Signaling by SCF-KIT / cytokine-mediated signaling pathway / SH3 domain binding / Signaling by CSF1 (M-CSF) in myeloid cells / G alpha (12/13) signalling events / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / insulin receptor signaling pathway / DAP12 signaling / regulation of cell population proliferation / RAF/MAP kinase cascade / Potential therapeutics for SARS / Ras protein signal transduction / protein heterodimerization activity / neuronal cell body
Similarity search - Function
Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factor, catalytic domain superfamily / Ras guanine nucleotide exchange factor domain superfamily / RasGEF domain ...Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factor, catalytic domain superfamily / Ras guanine nucleotide exchange factor domain superfamily / RasGEF domain / Ras guanine-nucleotide exchange factors catalytic domain profile. / Guanine nucleotide exchange factor for Ras-like small GTPases / Ras guanine-nucleotide exchange factors catalytic domain / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Histone-fold / PH-like domain superfamily
Similarity search - Domain/homology
Chem-NL0 / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsGunn, R.J. / Lawson, J.D. / Ketcham, J.M. / Marx, M.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction.
Authors: Ketcham, J.M. / Haling, J. / Khare, S. / Bowcut, V. / Briere, D.M. / Burns, A.C. / Gunn, R.J. / Ivetac, A. / Kuehler, J. / Kulyk, S. / Laguer, J. / Lawson, J.D. / Moya, K. / Nguyen, N. / ...Authors: Ketcham, J.M. / Haling, J. / Khare, S. / Bowcut, V. / Briere, D.M. / Burns, A.C. / Gunn, R.J. / Ivetac, A. / Kuehler, J. / Kulyk, S. / Laguer, J. / Lawson, J.D. / Moya, K. / Nguyen, N. / Rahbaek, L. / Saechao, B. / Smith, C.R. / Sudhakar, N. / Thomas, N.C. / Vegar, L. / Vanderpool, D. / Wang, X. / Yan, L. / Olson, P. / Christensen, J.G. / Marx, M.A.
History
DepositionApr 1, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2022Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.2Aug 10, 2022Group: 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 1.3Oct 18, 2023Group: 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: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5332
Polymers57,1031
Non-polymers4291
Water90150
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.792, 89.102, 172.316
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 Son of sevenless homolog 1 / SOS-1


Mass: 57103.285 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOS1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07889
#2: Chemical ChemComp-NL0 / 4-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(piperazin-1-yl)phthalazin-1-amine


Mass: 429.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26F3N5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / 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: 2.74 Å3/Da / Density % sol: 55.14 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 5-15% PEG 8000, 5-15% Ethanol, 100 mM Tris pH 8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.987 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 11, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.29→61.94 Å / Num. obs: 28762 / % possible obs: 98.8 % / Redundancy: 4.4 % / Biso Wilson estimate: 61.14 Å2 / CC1/2: 0.99 / Rpim(I) all: 0.04 / Net I/σ(I): 13.8
Reflection shellResolution: 2.29→2.37 Å / Num. unique obs: 2766 / CC1/2: 0.45 / Rpim(I) all: 2.6

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5OVI

5ovi


Resolution: 2.29→61.94 Å / SU ML: 0.474 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 37.1632
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2749 1339 4.78 %
Rwork0.2423 26666 -
obs0.2438 28005 95.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 70 Å2
Refinement stepCycle: LAST / Resolution: 2.29→61.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3796 0 31 50 3877
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00133922
X-RAY DIFFRACTIONf_angle_d0.40545322
X-RAY DIFFRACTIONf_chiral_restr0.0359584
X-RAY DIFFRACTIONf_plane_restr0.0036684
X-RAY DIFFRACTIONf_dihedral_angle_d10.82381492
LS refinement shellResolution: 2.29→2.37 Å
RfactorNum. reflection% reflection
Rfree0.6507 94 -
Rwork0.6279 2053 -
obs--75.18 %
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)
15.234574969210.707140422104-1.307281183363.424972045530.604908550536.09455825517-0.123846826761-0.0507913894945-0.1185906387810.528658649596-0.01272104002860.6734334532011.10852082687-0.06340878834440.198089290220.839514459504-0.1146513698330.008087377375350.5067118786950.02286518072140.6619418177380.936302034286-17.325051081322.7986291508
20.969365390713-0.229113600187-0.2617655775264.633866255162.309873704312.613620818790.07985520446460.141540894775-0.194925377019-0.0689758515053-0.1517095928650.4182576859280.0664667833384-0.2850303644990.07258926006120.321535720008-0.00103944190952-0.04190169843570.537169340051-0.0448341309180.4610945168622.52609804976-14.01828889419.68033652178
33.9116347767-0.8160533917080.2423888701416.285146801771.480063134076.006877414970.225048235330.46131088079-0.14626236305-1.19157137420.0161482083522-0.154395283036-0.689586856999-0.0628944543157-0.2201675313520.611028846432-0.00889088556790.07577064834340.561386176947-0.01640565113230.417035569899.319724946941.551542338363.90434973435
40.976470240393-1.22957481389-0.2585195063723.29941998003-0.4407517877182.147533745010.4215687141330.2163457729590.387242840404-0.928229778218-0.299214429392-0.365362693851-1.30437686803-0.0687485318721-0.1424651446531.389720047770.08840190856550.2440702169610.6383322336840.04779071242170.5497694667992.9312862926338.244260854916.1440972897
50.885532348928-0.255800014121-0.5354270758074.891236427622.481720397052.865550135330.245894475238-0.01561415649210.275945212515-0.238884800970.162022328798-0.636789831538-0.6862164303610.187304524331-0.4178049717740.621311143713-0.04407773061340.1000173349390.479847772136-0.01085189988310.5012034424727.0296205293731.278830280531.0284246319
60.5782217445480.176639695287-0.3504495914734.353046247552.260689027042.21249419705-0.0214994180312-0.02333993970040.05126979192350.2652843260240.02414407831690.1381940409690.0428348473203-0.1705707478380.01781181941170.440550470201-0.01208474510910.06521071761630.53763258173-0.01401800508010.426429306985-1.8901834370513.937862965332.2818559278
71.21594684347-0.0313717336637-1.583369448733.977770268410.247604654972.478613628540.201953234320.1983643528760.024595148327-1.380323398890.144363353798-0.493062917449-0.589112469336-0.121366664212-0.3252190685321.07734697170.01258375279120.2367973032960.7181766357110.07481470136580.6043095183419.0427031929532.045851370917.8397843561
82.68497283607-0.5373189774710.0431026388893.729769925280.5275215549194.033417145240.264909196909-0.169463674780.197579141433-0.2371114358030.315086597328-0.639075847817-1.183916377150.491632684421-0.5225578344710.910530402829-0.1850961175890.1413939300710.549819884878-0.09644282963350.76974116210212.112963584444.71702413137.1198917495
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 567 through 605 )567 - 6051 - 31
22chain 'A' and (resid 606 through 699 )606 - 69932 - 125
33chain 'A' and (resid 700 through 746 )700 - 746126 - 172
44chain 'A' and (resid 753 through 797 )753 - 797173 - 217
55chain 'A' and (resid 798 through 894 )798 - 894218 - 314
66chain 'A' and (resid 895 through 974 )895 - 974315 - 394
77chain 'A' and (resid 975 through 1001 )975 - 1001395 - 421
88chain 'A' and (resid 1002 through 1044 )1002 - 1044422 - 464

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