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- PDB-9zq7: Autoinhibited P-Rex2 -

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Basic information

Entry
Database: PDB / ID: 9zq7
TitleAutoinhibited P-Rex2
ComponentsPhosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein
KeywordsSIGNALING PROTEIN / Rho guanine-nucleotide exchange factor / autoinhibition
Function / homology
Function and homology information


negative regulation of TOR signaling / regulation of small GTPase mediated signal transduction / CDC42 GTPase cycle / RHOA GTPase cycle / protein serine/threonine kinase inhibitor activity / RAC1 GTPase cycle / guanyl-nucleotide exchange factor activity / GTPase activator activity / Regulation of PTEN stability and activity / intracellular signal transduction ...negative regulation of TOR signaling / regulation of small GTPase mediated signal transduction / CDC42 GTPase cycle / RHOA GTPase cycle / protein serine/threonine kinase inhibitor activity / RAC1 GTPase cycle / guanyl-nucleotide exchange factor activity / GTPase activator activity / Regulation of PTEN stability and activity / intracellular signal transduction / G protein-coupled receptor signaling pathway / plasma membrane / cytosol
Similarity search - Function
PREX2, DEP domain 1 / : / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / : / SOS1/NGEF-like PH domain ...PREX2, DEP domain 1 / : / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / : / SOS1/NGEF-like PH 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. / PDZ domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain / PDZ superfamily / PH-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.2 Å
AuthorsAnderson, L.K. / Cash, J.N.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM146664 United States
National Institutes of Health/National Center for Advancing Translational Sciences (NIH/NCATS)UL1 TR001860 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R24GM154185 United States
CitationJournal: J Biol Chem / Year: 2026
Title: The Rho guanine-nucleotide exchange factor P-Rex2 exhibits structural and regulatory features distinct from the related RhoGEF P-Rex1.
Authors: Lauren K Anderson / Rohan Marde / Grace Muma / Veda Nayak / Chi Phan / Sheng Li / Jennifer N Cash /
Abstract: Rho guanine-nucleotide exchange factors (RhoGEFs) activate small GTPases to drive cytoskeletal rearrangement, cell motility, and proliferation. The phosphatidylinositol-3,4,5-trisphosphate (PIP)- ...Rho guanine-nucleotide exchange factors (RhoGEFs) activate small GTPases to drive cytoskeletal rearrangement, cell motility, and proliferation. The phosphatidylinositol-3,4,5-trisphosphate (PIP)-dependent Rac exchanger (P-Rex) subfamily of RhoGEFs includes P-Rex1 and P-Rex2 which, when misregulated, contribute to cancer progression and metastasis. P-Rex activity is controlled by accessory domains that maintain the protein in a cytosolic, autoinhibited state until activated by the lipid PIP and G protein βγ subunits. While P-Rex1 autoinhibition has been structurally and biochemically characterized, P-Rex2 has remained largely unexplored. Furthermore, despite high sequence similarity and domain conservation, P-Rex homologs differ in substrate specificity and regulatory interactions, and the molecular basis for these divergences is unknown. Here, we have taken an integrative structural biology approach to investigate these gaps. Using cryo-EM, we determined the first structure of full-length P-Rex2 to moderate resolution, revealing that, while the overall structure closely resembles that of P-Rex1, there is a substantial repositioning of the N-terminal module relative to the C-terminal core. This may play a key role in precluding the intramolecular interactions between the N- and C-terminal domains that are observed in autoinhibited P-Rex1. Hydrogen-deuterium exchange mass spectrometry revealed that, unlike P-Rex1, P-Rex2 dynamics are unaffected by IP, the headgroup of PIP. SEC-SAXS data support that the N-terminal module itself is less dynamic, and biochemical assays show that P-Rex2 may be differently regulated by autoinhibition, likely through a mechanism divergent from P-Rex1. These findings uncover unique features in the molecular mechanisms of P-Rex2 regulation.
History
DepositionDec 17, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein


Theoretical massNumber of molelcules
Total (without water)184,5061
Polymers184,5061
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein / P-Rex2 / PtdIns(3 / 4 / 5)-dependent Rac exchanger 2 / DEP domain-containing protein 2


Mass: 184506.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PREX2, DEPDC2 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q70Z35
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-Rex2)
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.183 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293F
Buffer solutionpH: 8
Details: 20 mM HEPES (pH 8.0), 100 mM NaCl, 2 mM dithiothreitol (DTT), 0.07 mM n-Dodecyl-B-D-Maltoside (DDM)
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 2 / Num. of real images: 19792
Details: 12070 untilted micrographs and 7722 micrographs with 35 tilt
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameCategory
1Warpparticle selection
7Cootmodel fitting
8UCSF ChimeraXmodel fitting
13PHENIX3D reconstruction
26PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4322000
Details: 2184088 particles from tilted micrographs and 2137912 particles from untilted micrographs
3D reconstructionResolution: 5.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 215042 / Details: Average FSC of focused refinement maps / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Details: AlphaFold server used to generate individual initial models of the core and N-terminal module which were rigid body fit to the composite map and further refined in Coot.
Atomic model building
ID 3D fitting-IDChain residue rangeDetails (eV)Source nameType
1115-467P-Rex2 N-terminal moduleAlphaFoldin silico model
21473-1606P-Rex2 C-terminal coreAlphaFoldin silico model
RefinementHighest resolution: 5.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028468
ELECTRON MICROSCOPYf_angle_d0.37411384
ELECTRON MICROSCOPYf_dihedral_angle_d8.9793167
ELECTRON MICROSCOPYf_chiral_restr0.0371267
ELECTRON MICROSCOPYf_plane_restr0.0031444

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