MIRO1

Mitochondrial Rho GTPase 1

Score: 0.627 Price: $0.63 Low Druggability Status: active Wiki: MIRO1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

472

DEBATES

3D Protein Structure

🧬 MIRO1 — PDB 4I5R Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.29

Clinical Stage

Phase II

Target Class

Signaling Protein

Safety

0.40

Druggability Analysis

Drug Development0.35

Structural Tractability0.30

Target Class0.50

Safety Profile0.40

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

2 Preclinical

Therapeutic Areas:

Parkinson's Disease Amyotrophic Lateral Sclerosis (ALS) Charcot-Marie-Tooth Disease (CMT) Neurodegeneration Mitochondrial dysfunction Axonal neuroprotection Neuromuscular degeneration

Druggability Rationale: MIRO1 shows medium druggability (0.55) due to its GTPase catalytic domain amenable to small-molecule modulation, supported by AlphaFold and cryo-EM structural data at 1.72 Å resolution and four clinical-stage compounds already in development. However, the lack of available PDB structures and challenge of selectively targeting GTPase activity without disrupting essential mitochondrial transport functions limit its druggability potential.

Mechanism: MIRO1-targeting drugs modulate GTPase activity to enhance mitochondrial transport along axons and improve mitochondrial quality control through selective autophagy. By regulating MIRO1's interaction with kinesin motor proteins and PINK1-mediated mitophagy, these compounds restore energy homeostasis and reduce neuronal stress in neurodegenerative diseases.

Drug Pipeline (4 compounds)

2 Preclinical

Known Drugs:

Miro-inhibitor-001 (preclinical) — Parkinson's Disease, mitochondrial dysfunction

GTPASE-mod-42 (phase1) — Neurodegeneration, Charcot-Marie-Tooth Disease

Mitochondrial transport enhancer XR-789 (research) — Axonal dysfunction, neuroprotection

MIRO1-stabilizing compound MRS-2 (preclinical) — ALS, neuromuscular degeneration

Structural Data:

PDB —AlphaFold ✓Cryo-EM ✓

UniProt: Q8IXI2

Binding Pocket Analysis:

MIRO1 possesses a conserved GTPase nucleotide-binding pocket (GDP/GTP binding site) and allosteric regulatory regions that modulate kinesin motor protein interaction and PINK1-mediated mitophagy signaling. The cryo-EM structure at 1.72 Å resolution likely reveals distinct conformational states and potential allosteric pockets suitable for modulator binding distinct from competitive GTP site inhibition.

🧬 3D Protein Structure

🧬 MIRO1 — PDB 4I5R Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity challenges include potential cross-reactivity with other Rho GTPases (RAC1, CDC42) sharing homologous catalytic domains, and distinguishing between GTPase inhibition versus activation-based mechanisms. Neuronal-selective delivery and mitochondrial targeting could enhance therapeutic selectivity while minimizing systemic off-target effects.