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- PDB-6nfa: Vav1 inhibited by an allosteric inhibitor: Vav1 inhibitors block ... -

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Basic information

Entry
Database: PDB / ID: 6nfa
TitleVav1 inhibited by an allosteric inhibitor: Vav1 inhibitors block GEF activity
ComponentsProto-oncogene vav
KeywordsSIGNALING PROTEIN/INHIBITOR / GEF / Rac / Vav1 / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


phosphorylation-dependent protein binding / Azathioprine ADME / regulation of small GTPase mediated signal transduction / CD28 dependent Vav1 pathway / regulation of cell size / regulation of GTPase activity / NRAGE signals death through JNK / positive regulation of natural killer cell mediated cytotoxicity / Fc-gamma receptor signaling pathway involved in phagocytosis / Fc-epsilon receptor signaling pathway ...phosphorylation-dependent protein binding / Azathioprine ADME / regulation of small GTPase mediated signal transduction / CD28 dependent Vav1 pathway / regulation of cell size / regulation of GTPase activity / NRAGE signals death through JNK / positive regulation of natural killer cell mediated cytotoxicity / Fc-gamma receptor signaling pathway involved in phagocytosis / Fc-epsilon receptor signaling pathway / RHOG GTPase cycle / T cell differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / RHOA GTPase cycle / RAC2 GTPase cycle / vascular endothelial growth factor receptor signaling pathway / Erythropoietin activates RAS / GPVI-mediated activation cascade / RAC1 GTPase cycle / T cell costimulation / reactive oxygen species metabolic process / phosphotyrosine residue binding / FCERI mediated Ca+2 mobilization / guanyl-nucleotide exchange factor activity / neutrophil chemotaxis / VEGFR2 mediated vascular permeability / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / integrin-mediated signaling pathway / Regulation of signaling by CBL / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Signaling by SCF-KIT / Regulation of actin dynamics for phagocytic cup formation / platelet activation / VEGFA-VEGFR2 Pathway / Constitutive Signaling by Aberrant PI3K in Cancer / G alpha (12/13) signalling events / cell-cell junction / cell migration / cellular response to xenobiotic stimulus / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Potential therapeutics for SARS / intracellular signal transduction / immune response / G protein-coupled receptor signaling pathway / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
VAV1 protein, second SH3 domain / VAV1 protein, first SH3 domain / VAV1, SH2 domain / Vav, PH domain / Smooth muscle protein/calponin / Calmodulin-regulated spectrin-associated protein-like, Calponin-homology domain / CAMSAP CH domain / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Calponin homology domain ...VAV1 protein, second SH3 domain / VAV1 protein, first SH3 domain / VAV1, SH2 domain / Vav, PH domain / Smooth muscle protein/calponin / Calmodulin-regulated spectrin-associated protein-like, Calponin-homology domain / CAMSAP CH domain / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Calponin homology domain / Phorbol esters/diacylglycerol binding domain (C1 domain) / Calponin homology domain / CH domain superfamily / Calponin homology (CH) domain profile. / 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. / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / PH-like domain superfamily
Similarity search - Domain/homology
Chem-9K1 / Proto-oncogene vav
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.7 Å
AuthorsKnapp, M.S. / Elling, R.A. / Ornelas, E.
CitationJournal: To Be Published
Title: Allosteric Inhibitors of VAV1 Block Guanine Nucleotide Exchange Activity
Authors: Gerspacher, M. / Skaanderup, P.R.
History
DepositionDec 19, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proto-oncogene vav
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,1704
Polymers49,6801
Non-polymers4903
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area20250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.880, 67.641, 179.544
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 Proto-oncogene vav / Vav1 vav guanine nucleotide exchange factor 1


Mass: 49679.875 Da / Num. of mol.: 1 / Fragment: UNP residues 170-575
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VAV1, VAV / Production host: Escherichia coli (E. coli) / References: UniProt: P15498
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-9K1 / (2S)-2-{[3-(4-methylphenyl)imidazo[1,2-a]pyrazin-8-yl]amino}-3-(pyridin-3-yl)propan-1-ol


Mass: 359.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21N5O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O

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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: 2.25 Å3/Da / Density % sol: 45.43 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 16-22% v/v ethylene glycol, 0.1 M Tris, pH 7.3, 15% w/v PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 28, 2011
RadiationMonochromator: Liquid Nitrogen cooled Dual Crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→89.77 Å / Num. obs: 13081 / % possible obs: 100 % / Redundancy: 13.5 % / Biso Wilson estimate: 50.58 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.211 / Rpim(I) all: 0.06 / Rrim(I) all: 0.219 / Net I/σ(I): 14.7 / Num. measured all: 176945 / Scaling rejects: 22
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.7-2.8314.30.852427817020.9430.2330.8825.6100
8.96-89.7710.70.06447024380.9990.020.06726.999.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTERrefinement
XDSdata reduction
Aimless0.5.32data scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6NEW

6new


Resolution: 2.7→63.3 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.876 / SU R Cruickshank DPI: 3.881 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.328 / SU Rfree Cruickshank DPI: 0.325
RfactorNum. reflection% reflectionSelection details
Rfree0.242 568 4.36 %RANDOM
Rwork0.188 ---
obs0.19 13027 100 %-
Displacement parametersBiso max: 153.77 Å2 / Biso mean: 53.78 Å2 / Biso min: 11.32 Å2
Baniso -1Baniso -2Baniso -3
1-1.2825 Å20 Å20 Å2
2--8.0524 Å20 Å2
3----9.335 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 2.7→63.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3138 0 29 76 3243
Biso mean--26.99 41.51 -
Num. residues----386
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1187SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes89HARMONIC2
X-RAY DIFFRACTIONt_gen_planes466HARMONIC5
X-RAY DIFFRACTIONt_it3224HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion404SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3453SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3224HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg4330HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion18.68
LS refinement shellResolution: 2.7→2.92 Å / Rfactor Rfree error: 0 / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.3079 111 4.25 %
Rwork0.1952 2501 -
all0.1999 2612 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -1.0555 Å / Origin y: 8.2462 Å / Origin z: -24.156 Å
111213212223313233
T-0.0571 Å2-0.1086 Å20.0116 Å2--0.1389 Å2-0.0092 Å2---0.1734 Å2
L0.4214 °20.1686 °20.0096 °2-2.1013 °2-0.0681 °2--1.1882 °2
S0.1096 Å °-0.1211 Å °0.0095 Å °0.4365 Å °-0.1622 Å °0.0466 Å °0.2733 Å °-0.1017 Å °0.0526 Å °
Refinement TLS groupSelection details: { A|* }

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