7DUD

Crystal Structure of erWalK

Summary for 7DUD

• Entry DOI: 10.2210/pdb7dud/pdb
• Descriptor: Sensor protein kinase WalK (2 entities in total)
• Functional Keywords: walk, yycg, transferase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 2
• Total formula weight: 34168.49

Authors

Huang, W. (deposition date: 2021-01-08, release date: 2022-01-19, Last modification date: 2026-06-03)

Primary citation

Cheng, M.J.,Wu, Y.Y.,Zeng, H.,Zhang, T.H.,Hu, Y.X.,Liu, S.Y.,Cui, R.Q.,Hu, C.X.,Zou, Q.M.,Li, C.C.,Ye, W.C.,Huang, W.,Wang, L.
Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA.
Nat Commun, 15:5879-5879, 2024

PubMed Abstract: The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.

PubMed: 38997253
DOI: 10.1038/s41467-024-49629-8

Experimental method

X-RAY DIFFRACTION (1.95 Å)