8RW6

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

8RW6 の概要

• エントリーDOI: 10.2210/pdb8rw6/pdb
• 分子名称: Basic helix-loop-helix ARNT-like protein 1 (2 entities in total)
• 機能のキーワード: transcription factor, circadian rhythm, snc, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13189.99

構造登録者

Pu, H.,Rastinejad, F. (登録日: 2024-02-02, 公開日: 2025-02-05, 最終更新日: 2025-05-07)

主引用文献

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., 21:736-745, 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

実験手法

X-RAY DIFFRACTION (1.83 Å)