6H4M

TarP-UDP-GlcNAc-3RboP

6H4M の概要

• エントリーDOI: 10.2210/pdb6h4m/pdb
• 分子名称: Probable ss-1,3-N-acetylglucosaminyltransferase, [(2~{R},3~{S},4~{S})-2,3,4,5-tetrakis(oxidanyl)pentyl] [(2~{R},3~{R},4~{S})-2,3,4-tris(oxidanyl)-5-[oxidanyl-[(2~{R},3~{S},4~{S})-2,3,4-tris(oxidanyl)-5-phosphonooxy-pentoxy]phosphoryl]oxy-pentyl] hydrogen phosphate, URIDINE-DIPHOSPHATE-N-ACETYLGLUCOSAMINE, ... (7 entities in total)
• 機能のキーワード: staphylococcus aureus, wall teichoic acid, glycosyltransferase, gt-a fold, transferase
• 由来する生物種: Staphylococcus aureus (strain N315)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 494463.38

構造登録者

Guo, Y.,Stehle, T. (登録日: 2018-07-22, 公開日: 2018-09-26, 最終更新日: 2024-05-15)

主引用文献

Gerlach, D.,Guo, Y.,De Castro, C.,Kim, S.H.,Schlatterer, K.,Xu, F.F.,Pereira, C.,Seeberger, P.H.,Ali, S.,Codee, J.,Sirisarn, W.,Schulte, B.,Wolz, C.,Larsen, J.,Molinaro, A.,Lee, B.L.,Xia, G.,Stehle, T.,Peschel, A.
Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity.
Nature, 563:705-709, 2018

PubMed Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans. Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients. Previous vaccine development programs have not been successful. A large percentage of human antibodies against S. aureus target wall teichoic acid (WTA), a ribitol-phosphate (RboP) surface polymer modified with N-acetylglucosamine (GlcNAc). It is currently unknown whether the immune evasion capacities of MRSA are due to variation of dominant surface epitopes such as those associated with WTA. Here we show that a considerable proportion of the prominent healthcare-associated and livestock-associated MRSA clones CC5 and CC398, respectively, contain prophages that encode an alternative WTA glycosyltransferase. This enzyme, TarP, transfers GlcNAc to a different hydroxyl group of the WTA RboP than the standard enzyme TarS, with important consequences for immune recognition. TarP-glycosylated WTA elicits 7.5-40-fold lower levels of immunoglobulin G in mice than TarS-modified WTA. Consistent with this, human sera contained only low levels of antibodies against TarP-modified WTA. Notably, mice immunized with TarS-modified WTA were not protected against infection with tarP-expressing MRSA, indicating that TarP is crucial for the capacity of S. aureus to evade host defences. High-resolution structural analyses of TarP bound to WTA components and uridine diphosphate GlcNAc (UDP-GlcNAc) explain the mechanism of altered RboP glycosylation and form a template for targeted inhibition of TarP. Our study reveals an immune evasion strategy of S. aureus based on averting the immunogenicity of its dominant glycoantigen WTA. These results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defences.

PubMed: 30464342
DOI: 10.1038/s41586-018-0730-x

実験手法

X-RAY DIFFRACTION (2.73 Å)