A structural model of the Staphylococcus aureus ClfA-fibrinogen interaction opens new avenues for the design of anti-staphylococcal therapeutics.
A structural model of the Staphylococcus aureus ClfA-fibrinogen interaction opens new avenues for the design of anti-staphylococcal therapeutics.
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DOI：
10.1371/journal.ppat.1000226
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发表时间：
2008-11
期刊：
影响因子：
6.7
通讯作者：
Höök M
中科院分区：
文献类型：
--
作者：
Ganesh VK;Rivera JJ;Smeds E;Ko YP;Bowden MG;Wann ER;Gurusiddappa S;Fitzgerald JR;Höök M
金黄色葡萄球菌的纤维蛋白原（Fg）结合MSCRAMM成团因子A（ClfA）与纤维蛋白原（Fg）γ链的C-末端区域相互作用。ClfA是引起S.并且在脓毒性关节炎的小鼠模型以及感染性心内膜炎的兔和大鼠模型中被认为是毒力因子。我们在此报道了ClfA配体结合片段与模拟Fg结合位点的合成肽复合物的高分辨率晶体结构。Fg中结合ClfA所需的残基可从该结构和补充的生物化学研究中鉴定。此外，血小板整联蛋白αIIbβ3和ClfA结合Fg γ链中的相同片段，但这两种细胞结合蛋白识别共同靶向Fg片段中的不同残基。基于这些差异，我们已经鉴定了选择性拮抗ClfA-Fg相互作用的肽。ClfA-Fg结合机制是先前描述的表皮葡萄球菌SdrG-Fg相互作用的“停靠、锁定和闩锁”机制的变体。从分析ClfANFg肽复合物和鉴定选择性识别ClfA但不识别αIIbβ3的肽中获得的结构见解可能允许设计新型抗葡萄球菌药物。我们的结果还表明，具有相似结构组织的不同MSCRAMM可能起源于一个共同的祖先，但已经进化为适应特定的配体结构。 金黄色葡萄球菌(S.金黄色葡萄球菌）是一种常见的病原体，其可引起从人类的轻度皮肤感染到危及生命的脓毒症的一系列疾病。S.金黄色葡萄球菌在S.金黄色葡萄球菌病过程。这些细菌表面蛋白质之一是凝集因子A（ClfA），其结合到纤维蛋白原（Fg）的三条链之一的C-末端区域，Fg是在凝血中起关键作用的血液蛋白。我们进行了生化和结构研究以了解ClfA与Fg的结合机制，并确定Fg中与ClfA相互作用的残基。有趣的是，对血小板聚集和血栓形成很重要的血小板整联蛋白也与ClfA结合到Fg的相同区域。尽管这两种蛋白质在相同的区域结合，但识别的模式显著不同。利用这种识别上的差异，我们已经证明可以设计抑制ClfA-Fg相互作用但不干扰Fg与血小板整联蛋白相互作用的试剂。这打开了设计新型抗葡萄球菌治疗剂的领域。
The fibrinogen (Fg) binding MSCRAMM Clumping factor A (ClfA) from Staphylococcus aureus interacts with the C-terminal region of the fibrinogen (Fg) γ-chain. ClfA is the major virulence factor responsible for the observed clumping of S. aureus in blood plasma and has been implicated as a virulence factor in a mouse model of septic arthritis and in rabbit and rat models of infective endocarditis. We report here a high-resolution crystal structure of the ClfA ligand binding segment in complex with a synthetic peptide mimicking the binding site in Fg. The residues in Fg required for binding to ClfA are identified from this structure and from complementing biochemical studies. Furthermore, the platelet integrin αIIbβ3 and ClfA bind to the same segment in the Fg γ-chain but the two cellular binding proteins recognize different residues in the common targeted Fg segment. Based on these differences, we have identified peptides that selectively antagonize the ClfA-Fg interaction. The ClfA-Fg binding mechanism is a variant of the “Dock, Lock and Latch” mechanism previously described for the Staphylococcus epidermidis SdrG–Fg interaction. The structural insights gained from analyzing the ClfANFg peptide complex and identifications of peptides that selectively recognize ClfA but not αIIbβ3 may allow the design of novel anti-staphylococcal agents. Our results also suggest that different MSCRAMMs with similar structural organization may have originated from a common ancestor but have evolved to accommodate specific ligand structures. Staphylococcus aureus (S. aureus) is a common pathogen that can cause a range of diseases from mild skin infections to life-threatening sepsis in humans. Some surface proteins on S. aureus play important roles in the S. aureus disease process. One of these bacterial surface proteins is clumping factor A (ClfA) that binds to the C-terminal region of one of the three chains of fibrinogen (Fg), a blood protein that plays a key role in coagulation. We carried out biochemical and structural studies to understand the binding mechanism of ClfA to Fg and to define the residues in Fg that interact with ClfA. Interestingly, the platelet integrin, which is important for platelet aggregation and thrombi formation, also binds to the same region of Fg as ClfA. Despite the fact that the two proteins bind at the same region, the mode of recognition is significantly different. Exploiting this difference in recognition, we have demonstrated that agents could be designed that inhibit the ClfA–Fg interaction but do not interfere with the interaction of Fg with the platelet integrin. This opens the field for the design of a novel class of anti-staph therapeutics.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Bowden, M. Gabriela;Heuck, Alejandro P.;Hook, Magnus
通讯作者：
Hook, Magnus
影响因子：
11.4
作者：
Deivanayagam, CCS;Wann, ER;Narayana, SVL
通讯作者：
Narayana, SVL
影响因子：
3
作者：
KRISTINSSON, KG
通讯作者：
KRISTINSSON, KG
影响因子：
2.9
作者：
KLOCZEWIAK, M;TIMMONS, S;HAWIGER, J
通讯作者：
HAWIGER, J