Laboratory of Protein Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka City, 812-8582, Japan.
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
Sci Rep. 2024 Mar 5;14(1):5374. doi: 10.1038/s41598-024-55734-x.
In Gram-positive bacteria, sophisticated machineries to acquire the heme group of hemoglobin (Hb) have evolved to extract the precious iron atom contained in it. In the human pathogen Streptococcus pyogenes, the Shr protein is a key component of this machinery. Herein we present the crystal structure of hemoglobin-interacting domain 2 (HID2) of Shr bound to Hb. HID2 interacts with both, the protein and heme portions of Hb, explaining the specificity of HID2 for the heme-bound form of Hb, but not its heme-depleted form. Further mutational analysis shows little tolerance of HID2 to interfacial mutations, suggesting that its interaction surface with Hb could be a suitable candidate to develop efficient inhibitors abrogating the binding of Shr to Hb.
在革兰氏阳性菌中，已经进化出了复杂的机制来获取血红蛋白 (Hb) 的血红素基团，以提取其中所含的宝贵铁原子。在人类病原体酿脓链球菌中，Shr 蛋白是该机制的关键组成部分。本文介绍了 Shr 的血红蛋白相互作用结构域 2 (HID2) 与 Hb 结合的晶体结构。HID2 与 Hb 的蛋白和血红素部分相互作用，解释了 HID2 对 Hb 血红素结合形式的特异性，但不对其去血红素形式起作用。进一步的突变分析表明，HID2 对界面突变的容忍度很小，这表明其与 Hb 的相互作用表面可能是一个合适的候选物，可用于开发有效的抑制剂来阻止 Shr 与 Hb 的结合。
