PPARGC1A

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

Score: 0.593 Price: $0.59 Low Druggability Status: active Wiki: PPARGC1A

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

590

DEBATES

3D Protein Structure

🧬 PPARGC1A — PDB 3CS8 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.43

Clinical Stage

Approved

Target Class

Transcription Factor

Safety

0.40

Druggability Analysis

Drug Development0.75

Structural Tractability0.70

Target Class0.50

Safety Profile0.40

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (3 compounds)

1 Approved · 2 Preclinical

Therapeutic Areas:

Neurodegenerative diseases (Parkinson's disease, Alzheimer's disease) Huntington's disease Amyotrophic lateral sclerosis (ALS) Mitochondrial disorders Metabolic neurodegeneration Age-related cognitive decline

Druggability Rationale: PPARGC1A has medium druggability (0.55) due to its intrinsic challenge as a transcriptional coactivator lacking a deep orthosteric binding pocket, yet existing approved drugs (Bezafibrate) and investigational compounds (AICAR, ZLN005) demonstrate indirect and direct modulatory approaches are viable. The availability of high-resolution crystal structures (1.25 Å) and multiple PDB entries provide strong structural validation for rational drug design targeting allosteric or protein-protein interaction sites.

Mechanism: Small molecule modulator of transcriptional coactivator function

Drug Pipeline (3 compounds)

1 Approved · 2 Preclinical

Known Drugs:

Bezafibrate (approved) — PPAR agonist, indirectly activates PGC-1α, dyslipidemia

AICAR (investigational) — AMPK activator, upregulates PGC-1α expression

ZLN005 (preclinical) — Selective PGC-1α transcriptional activator

Structural Data:

PDB (7) ✓AlphaFold ✓Cryo-EM —

1XB7 3CS8 3D24 6LN4 8BF1+2 more

UniProt: Q9UBK2

Binding Pocket Analysis:

PGC-1α lacks a classical deep orthosteric binding pocket typical of kinases, instead featuring multiple intrinsically disordered regions and modular domains (LXXLL motifs, activation domains) suitable for allosteric modulation and protein-protein interaction disruption. High-resolution structures reveal potential allosteric pockets and regulatory interfaces that can be exploited for small molecule binding to modulate transcriptional coactivator function.

🧬 3D Protein Structure

🧬 PPARGC1A — PDB 3CS8 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 related coactivators (PGC-1β, PGC-1α4 isoforms) and off-target effects on broader PPAR signaling pathways when using indirect activators. Direct PGC-1α modulators like ZLN005 offer improved selectivity by targeting the transcriptional activation domain rather than upstream signaling cascades.