5XDV

Staphylococcus aureus FtsZ 12-316 G196S complexed with TXA6101

5XDV の概要

• エントリーDOI: 10.2210/pdb5xdv/pdb
• 関連するPDBエントリー: 5XDT 5XDU 5XDW
• 分子名称: Cell division protein FtsZ, GUANOSINE-5'-DIPHOSPHATE, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: cell division, gtpase, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Staphylococcus aureus (strain MRSA252)
• 細胞内の位置: Cytoplasm : Q6GHP9
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32843.51

構造登録者

Fujita, J.,Maeda, Y.,Mizohata, E.,Inoue, T.,Kaul, M.,Parhi, A.K.,LaVoie, E.J.,Pilch, D.S.,Matsumura, H. (登録日: 2017-03-30, 公開日: 2017-08-02, 最終更新日: 2023-11-22)

主引用文献

Fujita, J.,Maeda, Y.,Mizohata, E.,Inoue, T.,Kaul, M.,Parhi, A.K.,LaVoie, E.J.,Pilch, D.S.,Matsumura, H.
Structural Flexibility of an Inhibitor Overcomes Drug Resistance Mutations in Staphylococcus aureus FtsZ
ACS Chem. Biol., 12:1947-1955, 2017

PubMed Abstract: In the effort to combat antibiotic resistance, inhibitors of the essential bacterial protein FtsZ have emerged as a promising new class of compounds with clinical potential. One such FtsZ inhibitor (TXA707) is associated with potent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to current standard-of-care antibiotics. However, mutations in S. aureus FtsZ (SaFtsZ) that confer resistance to TXA707 have been observed, with mutations in the Gly196 and Gly193 residues being among the most prevalent. Here, we describe structural studies of an FtsZ inhibitor, TXA6101, which retains activity against MRSA isolates that express either G196S or G193D mutant FtsZ. We present the crystal structures of TXA6101 in complex with both wild-type SaFtsZ and G196S mutant SaFtsZ, as well the crystal structure of TXA707 in complex with wild-type SaFtsZ. Comparison of the three structures reveals a molecular basis for the differential targeting abilities of TXA6101 and TXA707. The greater structural flexibility of TXA6101 relative to TXA707 enables TXA6101 to avoid steric clashes with Ser196 and Asp193. Our structures also demonstrate that the binding of TXA6101 induces previously unobserved conformational rearrangements of SaFtsZ residues in the binding pocket. In aggregate, the structures reported in this work reveal key factors for overcoming drug resistance mutations in SaFtsZ and offer a structural basis for the design of FtsZ inhibitors with enhanced antibacterial potency and reduced susceptibility to mutational resistance.

PubMed: 28621933
DOI: 10.1021/acschembio.7b00323

実験手法

X-RAY DIFFRACTION (1.7 Å)