RAB27A

Ras-related protein Rab-27A

Score: 0.588 Price: $0.59 Low Druggability Status: active Wiki: RAB27A

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 RAB27A — PDB 2OT3 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.35

Clinical Stage

Phase II

Target Class

Signaling Protein

Safety

0.40

Druggability Analysis

Drug Development0.30

Structural Tractability0.85

Target Class0.50

Safety Profile0.40

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (1 compounds)

1 Preclinical

Therapeutic Areas:

Neurodegeneration (Alzheimer's disease, Parkinson's disease) Amyotrophic lateral sclerosis (ALS) Lysosomal storage disorders Exosome-mediated pathological protein transfer diseases Neuroinflammation

Druggability Rationale: RAB27A presents medium druggability (0.55 score) due to its GTPase activity domain and availability of 11 PDB structures at 2.0 Å resolution, which support structure-based drug design. However, the challenging kinetics of GTPase inhibition and the small GTPase protein class's inherent difficulty in targeting make this moderately challenging; Nexinhib20's preclinical status reflects the early-stage nature of this approach.

Mechanism: RAB27A inhibitors would block GTP binding or GTPase activity, preventing the recruitment of effector proteins required for vesicular trafficking and exosome biogenesis. This would reduce the release of extracellular vesicles and potentially modulate intercellular communication in disease states involving excessive exosome-mediated signaling or pathological cargo transfer.

Drug Pipeline (1 compounds)

1 Preclinical

Known Drugs:

Nexinhib20 (preclinical) — Rab27a inhibitor, blocks exosome secretion

Structural Data:

PDB (11) ✓AlphaFold ✓Cryo-EM —

6HUF 7OPP 7OPQ 7OPR 8P3G+6 more

UniProt: H3BS49

Binding Pocket Analysis:

The nucleotide binding pocket accommodates GTP/GDP and is typically characterized by conserved P-loop and switch regions; PDB structures (particularly 6HUF, 8P3G at high resolution) likely reveal both GTP-bound active and GDP-bound inactive conformations, enabling design of state-selective inhibitors targeting the switch II region or allosteric sites adjacent to the nucleotide pocket.

🧬 3D Protein Structure

🧬 RAB27A — PDB 2OT3 Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

RAB27A selectivity is a significant challenge due to homology with other RAB GTPases (RAB27B, RAB3A, RAB11); off-target inhibition could disrupt alternative vesicular trafficking pathways. Structure-guided design exploiting RAB27A-specific residues and allosteric pockets may improve selectivity over closely related isoforms.