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- PDB-6nf1: Vav1 inhibited by an allosteric inhibitor: Vav1 inhibitors block ... -

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Basic information

Entry
Database: PDB / ID: 6nf1
TitleVav1 inhibited by an allosteric inhibitor: Vav1 inhibitors block GEF activity
ComponentsProto-oncogene vav
KeywordsMETAL BINDING PROTEIN/INHIBITOR / GEF / Rac / Vav1 / inhibitor / METAL BINDING 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 / positive regulation of natural killer cell mediated cytotoxicity / regulation of GTPase activity / NRAGE signals death through JNK / 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 / positive regulation of natural killer cell mediated cytotoxicity / regulation of GTPase activity / NRAGE signals death through JNK / Fc-gamma receptor signaling pathway involved in phagocytosis / Fc-epsilon receptor signaling pathway / RHOG GTPase cycle / T cell differentiation / RHOA GTPase cycle / Interleukin-3, Interleukin-5 and GM-CSF signaling / 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 / Wheat Germ Agglutinin (Isolectin 2); domain 1 - #20 / Dbl Homology Domain; Chain A / Dbl homology (DH) 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 / Wheat Germ Agglutinin (Isolectin 2); domain 1 - #20 / Dbl Homology Domain; Chain A / Dbl homology (DH) domain / Calponin-like domain / Actin-binding Protein, T-fimbrin; domain 1 / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Wheat Germ Agglutinin (Isolectin 2); domain 1 / 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 / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / 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 / Src homology 3 domains / SH2 domain / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / PH-like domain superfamily / Roll / Up-down Bundle / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-9JY / Proto-oncogene vav
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.6 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 18, 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)68,1665
Polymers67,3831
Non-polymers7844
Water99155
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.134, 57.742, 89.419
Angle α, β, γ (deg.)90.000, 103.060, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Proto-oncogene vav


Mass: 67382.773 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VAV1, VAV / Production host: unidentified baculovirus / References: UniProt: P15498
#2: Chemical ChemComp-9JY / (2S)-3-[(3S)-1-(ethylsulfonyl)piperidin-3-yl]-2-{[3-(4-methylphenyl)imidazo[1,2-a]pyrazin-8-yl]amino}propan-1-ol


Mass: 457.589 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H31N5O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 55 / 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: 2.51 Å3/Da / Density % sol: 51.07 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 16-22% (v/v) Ethylene Glycol, 0.1M TRIS pH 7.3, and 15% (w/v) Polyethylene Glycol 8000.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 28, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.6→48.13 Å / Num. obs: 20808 / % possible obs: 99.8 % / Redundancy: 7.4 % / Biso Wilson estimate: 70.93 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.036 / Rrim(I) all: 0.097 / Net I/σ(I): 14.9
Reflection shellResolution: 2.6→2.9 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.705 / Num. unique obs: 5866 / CC1/2: 0.888 / Rpim(I) all: 0.276 / Rrim(I) all: 0.758 / % possible all: 99.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.3.3data scaling
PHASERphasing
BUSTERrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6NEW

6new


Resolution: 2.6→48.13 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.921 / SU R Cruickshank DPI: 0.66 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.61 / SU Rfree Blow DPI: 0.275 / SU Rfree Cruickshank DPI: 0.282
RfactorNum. reflection% reflectionSelection details
Rfree0.233 994 4.79 %RANDOM
Rwork0.193 ---
obs0.195 20756 99.8 %-
Displacement parametersBiso max: 169.51 Å2 / Biso mean: 69.69 Å2 / Biso min: 31.34 Å2
Baniso -1Baniso -2Baniso -3
1--13.8891 Å20 Å26.9987 Å2
2--7.3427 Å20 Å2
3---6.5464 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.6→48.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4410 0 46 55 4511
Biso mean--53.76 52.73 -
Num. residues----550
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1647SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes128HARMONIC2
X-RAY DIFFRACTIONt_gen_planes675HARMONIC5
X-RAY DIFFRACTIONt_it4571HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion580SEMIHARMONIC5
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_contact5054SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4571HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6172HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion2.89
X-RAY DIFFRACTIONt_other_torsion18.61
LS refinement shellResolution: 2.6→2.74 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2906 156 5.2 %
Rwork0.2246 2844 -
all0.228 3000 -
obs--99.9 %
Refinement TLS params.Method: refined / Origin x: 22.195 Å / Origin y: 5.5822 Å / Origin z: 18.3637 Å
111213212223313233
T-0.1274 Å2-0.0501 Å2-0.0205 Å2--0.1331 Å2-0.0313 Å2---0.1552 Å2
L0.6453 °2-0.0019 °20.388 °2-1.5176 °2-0.1782 °2--1.3828 °2
S-0.0008 Å °-0.0294 Å °0.0192 Å °0.0787 Å °0.0099 Å °-0.0299 Å °0.0569 Å °0.0152 Å °-0.0092 Å °
Refinement TLS groupSelection details: { A|* }

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