4YRD

Crystal structure of CapF with inhibitor 3-isopropenyl-tropolone

Summary for 4YRD

• Entry DOI: 10.2210/pdb4yrd/pdb
• Descriptor: Capsular polysaccharide synthesis enzyme Cap5F, ZINC ION, 2-hydroxy-3-(prop-1-en-2-yl)cyclohepta-2,4,6-trien-1-one, ... (4 entities in total)
• Functional Keywords: capf cupin capsular polysaccharide staphylococcus aureus, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Staphylococcus aureus (strain Mu50 / ATCC 700699)
• Total number of polymer chains: 2
• Total formula weight: 82379.43

Authors

Nakano, K.,Chigira, T.,Miyafusa, T.,Nagatoishi, S.,Caaveiro, J.M.M.,Tsumoto, K. (deposition date: 2015-03-15, release date: 2015-10-21, Last modification date: 2023-11-08)

Primary citation

Nakano, K.,Chigira, T.,Miyafusa, T.,Nagatoishi, S.,Caaveiro, J.M.,Tsumoto, K.
Discovery and characterization of natural tropolones as inhibitors of the antibacterial target CapF from Staphylococcus aureus.
Sci Rep, 5:15337-15337, 2015

PubMed Abstract: The rapid spread of antibiotic-resistance among pathogenic bacteria poses a serious risk for public health. The search for novel therapeutic strategies and antimicrobial compounds is needed to ameliorate this menace. The bifunctional metalloenzyme CapF is an antibacterial target produced by certain pathogenic bacteria essential in the biosynthetic route of capsular polysaccharide, a mucous layer on the surface of bacterium that facilitates immune evasion and infection. We report the first inhibitor of CapF from Staphylococcus aureus, which was identified by employing fragment-based methodologies. The hit compound 3-isopropenyl-tropolone inhibits the first reaction catalyzed by CapF, disrupting the synthesis of a key precursor of capsular polysaccharide. Isothermal titration calorimetry demonstrates that 3-isopropenyl-tropolone binds tightly (KD = 27 ± 7 μM) to the cupin domain of CapF. In addition, the crystal structure of the enzyme-inhibitor complex shows that the compound engages the essential Zn(2+) ion necessary for the first reaction catalyzed by the enzyme, explaining its inhibitory effect. Moreover, the tropolone compound alters the coordination sphere of the metal, leading to the overall destabilization of the enzyme. We propose 3-isopropenyl-tropolone as a precursor to develop stronger inhibitors for this family of enzymes to impair the synthesis of capsular polysaccharide in Staphylococcus aureus.

PubMed: 26471247
DOI: 10.1038/srep15337

Experimental method

X-RAY DIFFRACTION (2.44 Å)