更新于：2024-11-01

LukGH

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 LukGH 相关的药物

Berlimatoxumab

靶点

LukGH

作用机制

LukGH抑制剂

在研机构-

原研机构

Arsanis, Inc.

在研适应症-

非在研适应症

葡萄球菌感染

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 LukGH 相关的临床结果

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100 项与 LukGH 相关的转化医学

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0 项与 LukGH 相关的专利（医药）

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项与 LukGH 相关的文献（医药）

2021-10-31·Microbiology Spectrum2区 · 生物学

Further Insight into the Mechanism of Human PMN Lysis following Phagocytosis of Staphylococcus aureus

2区 · 生物学

Article

作者: DeLeo, Frank R. ; Malachowa, Natalia ; Kobayashi, Scott D. ; Otto, Michael ; Voyich, Jovanka M. ; Rungelrath, Viktoria ; Freedman, Brett A. ; Leung, Jacqueline M. ; Porter, Adeline R.

S. aureusstrain USA300 has the ability to cause rapid lysis of human neutrophils after phagocytosis. Although this phenomenon likely contributes to the success of USA300 as a human pathogen, our knowledge of the mechanism remains incomplete.

2020-01-07·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Molecular mechanism of leukocidin GH–integrin CD11b/CD18 recognition and species specificity

1区 · 综合性期刊

Article

作者: Djinović-Carugo, Kristina ; Svergun, Dmitri ; Trstenjak, Nikolina ; Milić, Dalibor ; Graewert, Melissa A. ; Badarau, Adriana ; Rouha, Harald ; Nagy, Eszter

Host–pathogen interactions are central to understanding microbial pathogenesis. The staphylococcal pore-forming cytotoxins hijack important immune molecules but little is known about the underlying molecular mechanisms of cytotoxin–receptor interaction and host specificity. Here we report the structures of a staphylococcal pore-forming cytotoxin, leukocidin GH (LukGH), in complex with its receptor (the α-I domain of complement receptor 3, CD11b-I), both for the human and murine homologs. We observe 2 binding interfaces, on the LukG and the LukH protomers, and show that human CD11b-I induces LukGH oligomerization in solution. LukGH binds murine CD11b-I weakly and is inactive toward murine neutrophils. Using a LukGH variant engineered to bind mouse CD11b-I, we demonstrate that cytolytic activity does not only require binding but also receptor-dependent oligomerization. Our studies provide an unprecedented insight into bicomponent leukocidin–host receptor interaction, enabling the development of antitoxin approaches and improved animal models to explore these approaches.

2019-01-31·Biochemical Journal

Adaptation of the Staphylococcus aureus leukocidin LukGH for the rabbit host by protein engineering

Article

作者: Zerbs, Manuel ; Stulik, Lukas ; Trstenjak, Nikolina ; Zmajkovic, Jakub ; Rouha, Harald ; Nagy, Eszter ; Badarau, Adriana

AbstractHost defense against Staphylococcus aureus greatly depends on bacterial clearance by phagocytic cells. LukGH (or LukAB) is the most potent staphylococcal leukocidin towards human phagocytes in vitro, but its role in pathogenesis is obscured by the lack of suitable small animal models because LukGH has limited or no cytotoxicity towards rodent and rabbit compared with human polymorphonuclear cells (PMNs) likely due to an impaired interaction with its cellular receptor, CD11b. We aimed at adapting LukGH for the rabbit host by improving binding to the rabbit homolog of CD11b, specifically its I-domain (CD11b-I). Targeted amino acid substitutions were introduced into the LukH polypeptide to map its receptor interaction site(s). We found that the binding affinity of LukGH variants to the human and rabbit CD11b-I correlated well with their PMN cytotoxicity. Importantly, we identified LukGH variants with significantly improved cytotoxicity towards rabbit PMNs, when expressed recombinantly (10–15-fold) or by engineered S. aureus strains. These findings support the development of small animal models of S. aureus infection with the potential for demonstrating the importance of LukGH in pathogenesis.