8RCW

Crystal structure of the Mycobacterium tuberculosis regulator VirS (N-terminal fragment 4-208) in complex with the lead compound SMARt751

8RCW の概要

• エントリーDOI: 10.2210/pdb8rcw/pdb
• 分子名称: HTH-type transcriptional regulator VirS, 4,4,4-tris(fluoranyl)-1-[4-(4-fluorophenyl)piperidin-1-yl]butan-1-one (3 entities in total)
• 機能のキーワード: arac family, transcription, tuberculosis, dna binding protein, in situ proteolysis
• 由来する生物種: Mycobacterium tuberculosis H37Rv
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51242.45

構造登録者

Grosse, C.,Sigoillot, M.,Megalizzi, V.,Tanina, A.,Willand, N.,Baulard, A.R.,Wintjens, R. (登録日: 2023-12-07, 公開日: 2024-04-10)

主引用文献

Grosse, C.,Sigoillot, M.,Megalizzi, V.,Tanina, A.,Willand, N.,Baulard, A.R.,Wintjens, R.
Crystal structure of the Mycobacterium tuberculosis VirS regulator reveals its interaction with the lead compound SMARt751.
J.Struct.Biol., 216:108090-108090, 2024

PubMed Abstract: Ethionamide (ETO) is a prodrug that is primarily used as a second-line agent in the treatment of tuberculosis. Among the bacterial ETO activators, the monooxygenase MymA has been recently identified, and its expression is regulated by the mycobacterial regulator VirS. The discovery of VirS ligands that can enhance mymA expression and thereby increase the antimycobacterial efficacy of ETO, has led to the development of a novel therapeutic strategy against tuberculosis. This strategy involves the selection of preclinical candidates, including SMARt751. We report the first crystal structure of the AraC-like regulator VirS, in complex with SMARt751, refined at 1.69 Å resolution. Crystals were obtained via an in situ proteolysis method in the requisite presence of SMARt751. The elucidated structure corresponds to the ligand-binding domain of VirS, adopting an α/β fold with structural similarities to H-NOX domains. Within the VirS structure, SMARt751 is situated in a completely enclosed hydrophobic cavity, where it forms hydrogen bonds with Asn11 and Asn149 as well as van der Waals contacts with various hydrophobic amino acids. Comprehensive structural comparisons within the AraC family of transcriptional regulators are conducted and analyzed to figure out the effects of the SMARt751 binding on the regulatory activity of VirS.

PubMed: 38548139
DOI: 10.1016/j.jsb.2024.108090

実験手法

X-RAY DIFFRACTION (1.692 Å)