7XI4

Crystal Structure of the NPAS4-ARNT heterodimer in complex with DNA

7XI4 の概要

• エントリーDOI: 10.2210/pdb7xi4/pdb
• 分子名称: Aryl hydrocarbon receptor nuclear translocator, Neuronal PAS domain protein 4, DNA (5'-D(*GP*GP*AP*GP*GP*TP*CP*GP*TP*GP*AP*GP*TP*GP*AP*T)-3'), ... (4 entities in total)
• 機能のキーワード: protein-dna complex, transcription
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 92485.40

構造登録者

Sun, X.N.,Jing, L.Q.,Li, F.W.,Wu, D.L. (登録日: 2022-04-12, 公開日: 2022-11-02, 最終更新日: 2023-11-29)

主引用文献

Sun, X.,Jing, L.,Li, F.,Zhang, M.,Diao, X.,Zhuang, J.,Rastinejad, F.,Wu, D.
Structures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers reveal new dimerization modalities in the bHLH-PAS transcription factor family.
Proc.Natl.Acad.Sci.USA, 119:e2208804119-e2208804119, 2022

PubMed Abstract: Neuronal PER-ARNT-SIM (PAS) domain protein 4 (NPAS4) is a protective transcriptional regulator whose dysfunction has been linked to a variety of neuropsychiatric and metabolic diseases. As a member of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) transcription factor family, NPAS4 is distinguished by an ability to form functional heterodimers with aryl hydrocarbon receptor nuclear translocator (ARNT) and ARNT2, both of which are also bHLH-PAS family members. Here, we describe the quaternary architectures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers in complexes involving DNA response elements. Our crystallographic studies reveal a uniquely interconnected domain conformation for the NPAS4 protein itself, as well as its differentially configured heterodimeric arrangements with both ARNT and ARNT2. Notably, the PAS-A domains of ARNT and ARNT2 exhibit variable conformations within these two heterodimers. The ARNT PAS-A domain also forms a set of interfaces with the PAS-A and PAS-B domains of NPAS4, different from those previously noted in ARNT heterodimers formed with other class I bHLH-PAS family proteins. Our structural observations together with biochemical and cell-based interrogations of these NPAS4 heterodimers provide molecular glimpses of the NPAS4 protein architecture and extend the known repertoire of heterodimerization patterns within the bHLH-PAS family. The PAS-B domains of NPAS4, ARNT, and ARNT2 all contain ligand-accessible pockets with appropriate volumes required for small-molecule binding. Given NPAS4's linkage to human diseases, the direct visualization of these PAS domains and the further understanding of their relative positioning and interconnections within the NPAS4-ARNT and NPAS4-ARNT2 heterodimers may provide a road map for therapeutic discovery targeting these complexes.

PubMed: 36343253
DOI: 10.1073/pnas.2208804119

実験手法

X-RAY DIFFRACTION (4.707 Å)