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Nat. Commun., 24 November 2024 | https://doi.org/10.1038/s41467-024-54551-0
Structural insight into the distinct regulatory mechanism of the HEPN–MNT toxin-antitoxin system in Legionella pneumophila
Chenglong Jin 1,2,8, Cha-Hee Jeon 1,3,8, Heung Wan Kim 1, Jin Mo Kang 1,3, Yuri Choi 4, Sung-Min Kang 5, Hyung Ho Lee 4, Do-Hee Kim 6,9,*, Byung Woo Han 1,3,9,* & Bong-Jin Lee 2,7,9,*
1The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
2MasterMediTech, Seoul, Republic of Korea.
3Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
4Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
5College of Pharmacy, Duksung Women’s University, Seoul, Republic of Korea.
6Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea.
7College of Pharmacy, Ajou University, Suwon, Republic of Korea.
8These authors contributed equally: Chenglong Jin, Cha-Hee Jeon.
9These authors jointly supervised this work: Do-Hee Kim, Byung Woo Han, Bong-Jin Lee.
2MasterMediTech, Seoul, Republic of Korea.
3Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
4Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
5College of Pharmacy, Duksung Women’s University, Seoul, Republic of Korea.
6Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea.
7College of Pharmacy, Ajou University, Suwon, Republic of Korea.
8These authors contributed equally: Chenglong Jin, Cha-Hee Jeon.
9These authors jointly supervised this work: Do-Hee Kim, Byung Woo Han, Bong-Jin Lee.
*Corresponding authors: correspondence to Do-Hee Kim, Byung Woo Han or Bong-Jin Lee
Abstract
HEPN–MNT, a type VII TA module, comprises the HEPN toxin and the MNT antitoxin, which acts as a nucleotidyltransferase that transfers the NMP moiety to the corresponding HEPN toxin, thereby interfering with its toxicity. Here, we report crystal structures of the Legionella pneumophila HEPN–MNT module, including HEPN, AMPylated HEPN, MNT, and the HEPN–MNT complex. Our structural analysis and biochemical assays, suggest that HEPN is a metal-dependent RNase and identify its active site residues. We also elucidate the oligomeric state of HEPN in solution. Interestingly, L. pneumophila MNT, which lacks a long C-terminal α4 helix, controls the toxicity of HEPN toxin via a distinct binding mode with HEPN. Finally, we propose a comprehensive regulatory mechanism of the L. pneumophila HEPN–MNT module based on structural and functional studies. These results provide insight into the type VII HEPN–MNT TA system.
논문정보
- Research article
- 2024년 11월 (BRIC 등록일 2024-12-12)
- 국내 연구진
- 생명과학 > 구조생물 및 생물물리학
관련 보도자료
레지오넬라균 유래 HEPN-MNT 독소-항독소 시스템의 독특한 조절 기전에 대한 구조적 고찰
본 연구에서는 최초로 제7 유형HEPN-MNT 독소 항독소 시스템의 새로운 기전을 규명하고 이를 구조적으로 설명하였습니다. 이로서 더욱 혁신적인 약물 개발의 타겟을 제시하였습니다. 본 연구팀이 밝힌 표적 단백질인 독소단백질 HEPN의 경우 매우 독특한 방법으로 활성을 조절함을 밝혀내었습니다. 첫째, HEPN 독소 단백질은 용액 상에서 이량체, 사량체로 존재하여 이량체 간의 결합이 가능하고 이러한 결합을 통하여 사량체가 되어 스스로 활성부위를 가리는 자가 억제 기전을 가집니다. 둘째, 항독소인 MNT의 번역 후 가공 과정에 의해 3~4개의 ATP를 전달받아 그로 인해 활성부위에 입체 장애가 유발되어 그 활성이 억제됩니다. 저희는 이러한 독소 단백질의 독특한 활성 조절 기전을 다양한 방식으로 규명 하였습니다.
- Bio통신원
- 2024. 12. 06
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