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- PDB-9ovj: Structure of human SHOC2 in complex with a small molecule inhibit... -

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Basic information

Entry
Database: PDB / ID: 9ovj
TitleStructure of human SHOC2 in complex with a small molecule inhibitor (R)-5
ComponentsLeucine-rich repeat protein SHOC-2
KeywordsSTRUCTURAL PROTEIN / SHOC2 / RAS / PP1C / MAPK / Inhibitor / Complex
Function / homology
Function and homology information


cellular response to growth hormone stimulus / negative regulation of neural precursor cell proliferation / protein phosphatase type 1 complex / volume-sensitive anion channel activity / nerve growth factor signaling pathway / cyclic-GMP-AMP transmembrane import across plasma membrane / protein phosphatase 1 binding / protein phosphatase regulator activity / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...cellular response to growth hormone stimulus / negative regulation of neural precursor cell proliferation / protein phosphatase type 1 complex / volume-sensitive anion channel activity / nerve growth factor signaling pathway / cyclic-GMP-AMP transmembrane import across plasma membrane / protein phosphatase 1 binding / protein phosphatase regulator activity / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of Ras protein signal transduction / regulation of MAPK cascade / negative regulation of neuron differentiation / fibroblast growth factor receptor signaling pathway / positive regulation of neuron differentiation / RAF activation / positive regulation of neuron projection development / protein phosphatase binding / intracellular signal transduction / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
: / : / Leucine-rich repeat region / Leucine-rich repeats, bacterial type / Leucine-rich repeat, SDS22-like subfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
: / : / Leucine-rich repeat protein SHOC-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 Å
AuthorsDhembi, A. / Hauseman, Z.J. / King, D.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
Citation
Journal: Nature / Year: 2025
Title: Targeting the SHOC2-RAS interaction in RAS-mutant cancers.
Authors: Hauseman, Z.J. / Stauffer, F. / Beyer, K.S. / Molle, S. / Cavicchioli, E. / Marchand, J.R. / Fodor, M. / Viscomi, J. / Dhembi, A. / Katz, S. / Faggion, B. / Lanter, M. / Kerr, G. / ...Authors: Hauseman, Z.J. / Stauffer, F. / Beyer, K.S. / Molle, S. / Cavicchioli, E. / Marchand, J.R. / Fodor, M. / Viscomi, J. / Dhembi, A. / Katz, S. / Faggion, B. / Lanter, M. / Kerr, G. / Schildknecht, D. / Handl, C. / Maddalo, D. / Pissot Soldermann, C. / Brady, J. / Shrestha, O. / Nguyen, Z. / Leder, L. / Cremosnik, G. / Lopez Romero, S. / Hassiepen, U. / Stams, T. / Linder, M. / Galli, G.G. / Guthy, D.A. / King, D.A. / Maira, S.M. / Thoma, C.R. / Ehmke, V. / Tordella, L.
#1: Journal: Nature / Year: 2025
Title: Targeting the SHOC2-RAS interaction in RAS-mutant cancers.
Authors: Hauseman, Z.J. / Stauffer, F. / Beyer, K.S. / Molle, S. / Cavicchioli, E. / Marchand, J.R. / Fodor, M. / Viscomi, J. / Dhembi, A. / Katz, S. / Faggion, B. / Lanter, M. / Kerr, G. / ...Authors: Hauseman, Z.J. / Stauffer, F. / Beyer, K.S. / Molle, S. / Cavicchioli, E. / Marchand, J.R. / Fodor, M. / Viscomi, J. / Dhembi, A. / Katz, S. / Faggion, B. / Lanter, M. / Kerr, G. / Schildknecht, D. / Handl, C. / Maddalo, D. / Pissot Soldermann, C. / Brady, J. / Shrestha, O. / Nguyen, Z. / Leder, L. / Cremosnik, G. / Lopez Romero, S. / Hassiepen, U. / Stams, T. / Linder, M. / Galli, G.G. / Guthy, D.A. / King, D.A. / Maira, S.M. / Thoma, C.R. / Ehmke, V. / Tordella, L.
History
DepositionMay 30, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Leucine-rich repeat protein SHOC-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,2783
Polymers56,7381
Non-polymers5402
Water1,08160
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)37.839, 70.137, 199.041
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 Leucine-rich repeat protein SHOC-2 / Protein soc-2 homolog / Protein sur-8 homolog


Mass: 56737.582 Da / Num. of mol.: 1 / Fragment: residues 80-582
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHOC2, KIAA0862 / Plasmid: pFastBac1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UQ13
#2: Chemical ChemComp-A1CF1 / (2R)-{2-[(4-chloro[1,1'-biphenyl]-3-yl)methoxy]phenyl}[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]acetic acid


Mass: 500.930 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H21ClN2O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.32 Å3/Da / Density % sol: 47.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: See reference. Crystals of apo SHOC2 in space group p212121 were incubated with compound and harvested. 0.05 M Tris (7.0), 40% (v/v) Pentaerythritol Propoxylate 5/4 PO/OH, 0.2 M KCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Dec 12, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.676→66.15 Å / Num. obs: 15738 / % possible obs: 100 % / Redundancy: 9.7 % / Biso Wilson estimate: 42.16 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.223 / Net I/σ(I): 9.4
Reflection shellResolution: 2.676→2.685 Å / Redundancy: 10.3 % / Rmerge(I) obs: 1.528 / Mean I/σ(I) obs: 2 / Num. unique obs: 158 / CC1/2: 0.703 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHASERphasing
autoPROCdata processing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.68→40.58 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.0345
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2752 770 4.9 %
Rwork0.1941 14959 -
obs0.1981 15729 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.01 Å2
Refinement stepCycle: LAST / Resolution: 2.68→40.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3916 0 37 60 4013
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00854013
X-RAY DIFFRACTIONf_angle_d1.04285440
X-RAY DIFFRACTIONf_chiral_restr0.0501656
X-RAY DIFFRACTIONf_plane_restr0.0065692
X-RAY DIFFRACTIONf_dihedral_angle_d17.63921550
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.68-2.880.40481430.27542925X-RAY DIFFRACTION99.97
2.88-3.170.31091670.26072933X-RAY DIFFRACTION100
3.17-3.630.31621420.22142951X-RAY DIFFRACTION100
3.63-4.570.24661600.15652980X-RAY DIFFRACTION99.94
4.57-40.580.22841580.16443170X-RAY DIFFRACTION99.94
Refinement TLS params.Method: refined / Origin x: 4.36870494068 Å / Origin y: -8.14613145464 Å / Origin z: -31.3238527692 Å
111213212223313233
T0.422508475282 Å2-0.000795392458147 Å20.0188347927606 Å2-0.390459309883 Å2-0.0205183294027 Å2--0.321877342652 Å2
L0.379160414598 °20.116839844071 °2-0.131471582366 °2-0.67997747536 °2-0.496893019689 °2--0.629603318454 °2
S0.00624125947121 Å °0.0279391372396 Å °-0.0174198413633 Å °-0.0549365257007 Å °-0.0487270561581 Å °0.00352136553378 Å °-0.013807740868 Å °0.0258623884135 Å °0.0417153363314 Å °
Refinement TLS groupSelection details: all

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