3T07

Crystal structure of S. aureus Pyruvate Kinase in complex with a naturally occurring bis-indole alkaloid

3T07 の概要

• エントリーDOI: 10.2210/pdb3t07/pdb
• 関連するPDBエントリー: 3T05 3T0T
• 分子名称: Pyruvate kinase, PHOSPHATE ION, (3S,5R)-3,5-bis(6-bromo-1H-indol-3-yl)piperazin-2-one (3 entities in total)
• 機能のキーワード: tetramer, ligand, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Staphylococcus aureus subsp. aureus
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 263438.99

構造登録者

Worrall, L.J.,Vuckovic, M.,Strynadka, N.C.J. (登録日: 2011-07-19, 公開日: 2011-10-26, 最終更新日: 2024-02-28)

主引用文献

Zoraghi, R.,Worrall, L.,See, R.H.,Strangman, W.,Popplewell, W.L.,Gong, H.,Samaai, T.,Swayze, R.D.,Kaur, S.,Vuckovic, M.,Finlay, B.B.,Brunham, R.C.,McMaster, W.R.,Davies-Coleman, M.T.,Strynadka, N.C.,Andersen, R.J.,Reiner, N.E.
Methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as a target for bis-indole alkaloids with antibacterial activities.
J.Biol.Chem., 286:44716-44725, 2011

PubMed Abstract: Novel classes of antimicrobials are needed to address the emergence of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). We have recently identified pyruvate kinase (PK) as a potential novel drug target based upon it being an essential hub in the MRSA interactome (Cherkasov, A., Hsing, M., Zoraghi, R., Foster, L. J., See, R. H., Stoynov, N., Jiang, J., Kaur, S., Lian, T., Jackson, L., Gong, H., Swayze, R., Amandoron, E., Hormozdiari, F., Dao, P., Sahinalp, C., Santos-Filho, O., Axerio-Cilies, P., Byler, K., McMaster, W. R., Brunham, R. C., Finlay, B. B., and Reiner, N. E. (2011) J. Proteome Res. 10, 1139-1150; Zoraghi, R., See, R. H., Axerio-Cilies, P., Kumar, N. S., Gong, H., Moreau, A., Hsing, M., Kaur, S., Swayze, R. D., Worrall, L., Amandoron, E., Lian, T., Jackson, L., Jiang, J., Thorson, L., Labriere, C., Foster, L., Brunham, R. C., McMaster, W. R., Finlay, B. B., Strynadka, N. C., Cherkasov, A., Young, R. N., and Reiner, N. E. (2011) Antimicrob. Agents Chemother. 55, 2042-2053). Screening of an extract library of marine invertebrates against MRSA PK resulted in the identification of bis-indole alkaloids of the spongotine (A), topsentin (B, D), and hamacanthin (C) classes isolated from the Topsentia pachastrelloides as novel bacterial PK inhibitors. These compounds potently and selectively inhibited both MRSA PK enzymatic activity and S. aureus growth in vitro. The most active compounds, cis-3,4-dihyrohyrohamacanthin B (C) and bromodeoxytopsentin (D), were identified as highly potent MRSA PK inhibitors (IC(50) values of 16-60 nM) with at least 166-fold selectivity over human PK isoforms. These novel anti-PK natural compounds exhibited significant antibacterial activities against S. aureus, including MRSA (minimal inhibitory concentrations (MIC) of 12.5 and 6.25 μg/ml, respectively) with selectivity indices (CC(50)/MIC) >4. We also report the discrete structural features of the MRSA PK tetramer as determined by x-ray crystallography, which is suitable for selective targeting of the bacterial enzyme. The co-crystal structure of compound C with MRSA PK confirms that the latter is a target for bis-indole alkaloids. It elucidates the essential structural requirements for PK inhibitors in "small" interfaces that provide for tetramer rigidity and efficient catalytic activity. Our results identified a series of natural products as novel MRSA PK inhibitors, providing the basis for further development of potential novel antimicrobials.

PubMed: 22030393
DOI: 10.1074/jbc.M111.289033

実験手法

X-RAY DIFFRACTION (3.3 Å)