Structural basis for the recognition of human hemoglobin by the heme-acquisition protein Shr from Streptococcus pyogenes

Akinobu Senoo; Masato Hoshino; Toshiki Shiomi; Makoto Nakakido; Satoru Nagatoishi; Daisuke Kuroda; Ichiro Nakagawa; Jeremy R H Tame; Jose M M Caaveiro; Kouhei Tsumoto

doi:10.1038/s41598-024-55734-x

Structural basis for the recognition of human hemoglobin by the heme-acquisition protein Shr from Streptococcus pyogenes

Sci Rep. 2024 Mar 5;14(1):5374. doi: 10.1038/s41598-024-55734-x.

Authors

Akinobu Senoo^{1

2}, Masato Hoshino³, Toshiki Shiomi¹, Makoto Nakakido³, Satoru Nagatoishi⁴, Daisuke Kuroda⁵, Ichiro Nakagawa⁶, Jeremy R H Tame⁷, Jose M M Caaveiro^{8

9}, Kouhei Tsumoto^{10

11

12}

Affiliations

¹ Laboratory of Protein Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka City, 812-8582, Japan.
² Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
³ Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
⁴ Medical Device Development and Regulation Research Center, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
⁵ Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
⁶ Department of Microbiology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
⁷ Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro, Yokohama, Kanagawa, 230-0045, Japan.
⁸ Laboratory of Protein Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka City, 812-8582, Japan. jose@phar.kyushu-u.ac.jp.
⁹ Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. jose@phar.kyushu-u.ac.jp.
¹⁰ Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. tsumoto@bioeng.t.u-tokyo.ac.jp.
¹¹ Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. tsumoto@bioeng.t.u-tokyo.ac.jp.
¹² The Institute of Medical Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8629, Japan. tsumoto@bioeng.t.u-tokyo.ac.jp.

Abstract

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.

Keywords: Streptococcus pyogenes; Heme; Heme acquisition; Hemoglobin; Host–pathogen interaction; MD simulations; Protein–protein interaction; Surface plasmon resonance; X-ray crystallography.

MeSH terms

Heme
Hemeproteins* / genetics
Humans
Iron
Recognition, Psychology
Streptococcus pyogenes / genetics

Substances

Hemeproteins
Heme
Iron

Abstract

MeSH terms

Substances

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