8RW6

Human Brain and muscle ARNT-like 1 (BMAL1_HUMAN) PAS-B domain

Summary for 8RW6

• Entry DOI: 10.2210/pdb8rw6/pdb
• Descriptor: Basic helix-loop-helix ARNT-like protein 1 (2 entities in total)
• Functional Keywords: transcription factor, circadian rhythm, snc, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 13189.99

Authors

Pu, H.,Rastinejad, F. (deposition date: 2024-02-02, release date: 2025-02-05, Last modification date: 2025-04-09)

Primary citation

Pu, H.,Bailey, L.C.,Bauer, L.G.,Voronkov, M.,Baxter, M.,Huber, K.V.M.,Khorasanizadeh, S.,Ray, D.,Rastinejad, F.
Pharmacological targeting of BMAL1 modulates circadian and immune pathways.
Nat.Chem.Biol., 2025

PubMed Abstract: The basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) proteins BMAL1 and CLOCK heterodimerize to form the master transcription factor governing rhythmic gene expression. Owing to connections between circadian regulation and numerous physiological pathways, targeting the BMAL1-CLOCK complex pharmacologically is an attractive entry point for intervening in circadian-related processes. In this study, we developed a small molecule, Core Circadian Modulator (CCM), that targets the cavity in the PASB domain of BMAL1, causing it to expand, leading to conformational changes in the PASB domain and altering the functions of BMAL1 as a transcription factor. Biochemical, structural and cellular investigations validate the high level of selectivity of CCM in engaging BMAL1, enabling direct access to BMAL1-CLOCK cellular activities. CCM induces dose-dependent alterations in PER2-Luc oscillations and orchestrates the downregulation of inflammatory and phagocytic pathways in macrophages. These findings collectively reveal that the BMAL1 protein architecture is inherently configured to enable the binding of chemical ligands for functional modulation.

PubMed: 40133642
DOI: 10.1038/s41589-025-01863-x

Experimental method

X-RAY DIFFRACTION (1.83 Å)