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- PDB-8p3g: Fusion hSlp2-a_Rab27A bound to covalent hit fragment IMP-1704 -

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Basic information

Entry
Database: PDB / ID: 8p3g
TitleFusion hSlp2-a_Rab27A bound to covalent hit fragment IMP-1704
ComponentsSynaptotagmin-like protein 2,Ras-related protein Rab-27A
KeywordsCYTOSOLIC PROTEIN / Small GTPase / Targeted Covalent Inhibitors / High Throughput screening / Drug Discovery / Vesicle trafficking / Breast Cancer
Function / homology
Function and homology information


multivesicular body organization / cytotoxic T cell degranulation / positive regulation of constitutive secretory pathway / positive regulation of regulated secretory pathway / melanosome localization / natural killer cell degranulation / exosomal secretion / melanosome transport / Weibel-Palade body / neurexin family protein binding ...multivesicular body organization / cytotoxic T cell degranulation / positive regulation of constitutive secretory pathway / positive regulation of regulated secretory pathway / melanosome localization / natural killer cell degranulation / exosomal secretion / melanosome transport / Weibel-Palade body / neurexin family protein binding / exocytic vesicle / melanocyte differentiation / multivesicular body sorting pathway / myosin V binding / RAB geranylgeranylation / melanosome membrane / multivesicular body membrane / RAB GEFs exchange GTP for GDP on RABs / complement-dependent cytotoxicity / vesicle docking involved in exocytosis / positive regulation of reactive oxygen species biosynthetic process / synaptic vesicle transport / Insulin processing / phosphatidylserine binding / Regulation of MITF-M-dependent genes involved in pigmentation / exocytosis / antigen processing and presentation / positive regulation of exocytosis / protein secretion / photoreceptor outer segment / phosphatase binding / positive regulation of phagocytosis / vesicle-mediated transport / phosphatidylinositol-4,5-bisphosphate binding / small monomeric GTPase / secretory granule / intracellular protein transport / G protein activity / small GTPase binding / specific granule lumen / GDP binding / blood coagulation / melanosome / late endosome / lysosome / apical plasma membrane / protein domain specific binding / GTPase activity / dendrite / Neutrophil degranulation / positive regulation of gene expression / GTP binding / Golgi apparatus / extracellular exosome / extracellular region / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Synaptotagmin-like 1-5, C2B domain / Rab27a/b / FYVE-type zinc finger / FYVE-type zinc finger / Rab-binding domain / Rab-binding domain profile. / : / small GTPase Rab1 family profile. / Protein kinase C conserved region 2 (CalB) / C2 domain ...Synaptotagmin-like 1-5, C2B domain / Rab27a/b / FYVE-type zinc finger / FYVE-type zinc finger / Rab-binding domain / Rab-binding domain profile. / : / small GTPase Rab1 family profile. / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain / C2 domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / C2 domain superfamily / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / : / Ras-related protein Rab-27A / Synaptotagmin-like protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 Å
AuthorsDe Vita, E. / Brustur, D. / Tersa, M. / Petracca, R. / Morgan, R.M.L. / Lanyon-Hogg, T. / Norman, J.C. / Cota, E. / Tate, E.W.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC29637/A20781 United Kingdom
CitationJournal: To Be Published
Title: Targeted covalent inhibitors of the small GTPase Rab27A
Authors: De Vita, E. / Brustur, D. / Tersa, M. / Petracca, R. / Morgan, R.M.L. / Lanyon-Hogg, T. / Norman, J.C. / Cota, E. / Tate, E.W.
History
DepositionMay 17, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 20, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Synaptotagmin-like protein 2,Ras-related protein Rab-27A
B: Synaptotagmin-like protein 2,Ras-related protein Rab-27A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,13115
Polymers51,8282
Non-polymers2,30213
Water5,549308
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6710 Å2
ΔGint-46 kcal/mol
Surface area19230 Å2
Unit cell
Length a, b, c (Å)62.299, 76.031, 118.846
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Synaptotagmin-like protein 2,Ras-related protein Rab-27A / Breast cancer-associated antigen SGA-72M / Exophilin-4 / Rab-27 / GTP-binding protein Ram


Mass: 25914.211 Da / Num. of mol.: 2 / Mutation: Q78L,C188S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SYTL2, KIAA1597, SGA72M, SLP2, SLP2A, RAB27A, RAB27
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q9HCH5, UniProt: P51159, small monomeric GTPase

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Non-polymers , 5 types, 321 molecules

#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-WTU / ~{N}-(4-pyrrolidin-1-ylsulfonylphenyl)propanamide / WT6


Mass: 282.359 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H18N2O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.9 Å3/Da / Density % sol: 57.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.15 M NH4SO4, 0.1 M MES, pH6.0, 15% PEG 4K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jul 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.13→59.42 Å / Num. obs: 32270 / % possible obs: 99.72 % / Redundancy: 2 % / CC1/2: 0.981 / Net I/σ(I): 4.2
Reflection shellResolution: 2.13→2.206 Å / Num. unique obs: 3161 / CC1/2: 0.344

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Processing

Software
NameVersionClassification
PHENIX(1.17_3644: ???)refinement
xia2data reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.13→59.42 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 24.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2412 1614 5.01 %
Rwork0.1903 --
obs0.1929 32210 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.13→59.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3363 0 108 308 3779
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073579
X-RAY DIFFRACTIONf_angle_d0.9194822
X-RAY DIFFRACTIONf_dihedral_angle_d26.24507
X-RAY DIFFRACTIONf_chiral_restr0.046519
X-RAY DIFFRACTIONf_plane_restr0.004601
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.13-2.190.30661330.26072473X-RAY DIFFRACTION99
2.19-2.260.3141220.24862488X-RAY DIFFRACTION100
2.26-2.340.30711350.22882533X-RAY DIFFRACTION100
2.34-2.440.31871380.22182510X-RAY DIFFRACTION100
2.44-2.550.27761390.20272504X-RAY DIFFRACTION100
2.55-2.680.26681120.19692548X-RAY DIFFRACTION100
2.68-2.850.25181220.19892559X-RAY DIFFRACTION100
2.85-3.070.2421340.19022547X-RAY DIFFRACTION100
3.07-3.380.21361380.1772544X-RAY DIFFRACTION100
3.38-3.870.23511510.16912555X-RAY DIFFRACTION100
3.87-4.870.18461270.14892620X-RAY DIFFRACTION100
4.88-59.420.22781630.22715X-RAY DIFFRACTION100

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