8CIX

DNA-polymerase sliding clamp (DnaN) from Escherichia coli in complex with Griselimycin.

8CIX の概要

• エントリーDOI: 10.2210/pdb8cix/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002311
• 分子名称: Beta sliding clamp, Griselimycin, GLYCEROL, ... (8 entities in total)
• 機能のキーワード: dnan, sliding clamp, dna-polymerase beta subunit, antibiotic, natural product, anti-tuberculosis, transferase
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 42779.19

構造登録者

Fu, C.,Liu, Y.,Walt, C.,Bader, C.,Rasheed, S.,Lukat, P.,Neuber, M.,Blankenfeldt, W.,Kalinina, O.,Mueller, R. (登録日: 2023-02-11, 公開日: 2023-11-29, 最終更新日: 2024-02-07)

主引用文献

Fu, C.,Liu, Y.,Walt, C.,Rasheed, S.,Bader, C.D.,Lukat, P.,Neuber, M.,Haeckl, F.P.J.,Blankenfeldt, W.,Kalinina, O.V.,Muller, R.
Elucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins.
Nat Commun, 15:791-791, 2024

PubMed Abstract: DNA polymerase III sliding clamp (DnaN) was recently validated as a new anti-tuberculosis target employing griselimycins. Three (2 S,4 R)-4-methylproline moieties of methylgriselimycin play significant roles in target binding and metabolic stability. Here, we identify the mycoplanecin biosynthetic gene cluster by genome mining using bait genes from the 4-methylproline pathway. We isolate and structurally elucidate four mycoplanecins comprising scarce homo-amino acids and 4-alkylprolines. Evaluating mycoplanecin E against Mycobacterium tuberculosis surprisingly reveals an excitingly low minimum inhibition concentration at 83 ng/mL, thus outcompeting griselimycin by approximately 24-fold. We show that mycoplanecins bind DnaN with nanomolar affinity and provide a co-crystal structure of mycoplanecin A-bound DnaN. Additionally, we reconstitute the biosyntheses of the unusual L-homoleucine, L-homonorleucine, and (2 S,4 R)-4-ethylproline building blocks by characterizing in vitro the full set of eight enzymes involved. The biosynthetic study, bioactivity evaluation, and drug target validation of mycoplanecins pave the way for their further development to tackle multidrug-resistant mycobacterial infections.

PubMed: 38278788
DOI: 10.1038/s41467-024-44953-5

実験手法

X-RAY DIFFRACTION (1.76 Å)