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연세대학교, Oregon Health & Science University

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Nat. Commun., Published: 01 July 2025 | https://doi.org/10.1038/s41467-025-61169-3 Structural and functional insights of AmpG in muropeptide transport and multiple β-lactam antibiotics resistance

Nienping Chang^1,11, Hoyoung Kim^1,2,11, Uijin Kim^1,11, Yongju Cho¹, Youngki Yoo^1,3, Hyunsook Lee⁴, Ji Won Kim⁵, Min Sung Kim^6,7, Jaeho Lee⁸, Young-Lag Cho⁸, Kitae Kim⁹, Dongeun Yong^4,12 & Hyun-Soo Cho^1,2,10,12

¹Department of Systems Biology and Division of Life Sciences, Yonsei University, 50 Yonsei-ro, Seoul, Republic of Korea.
²Vollum Institute, Oregon Health & Science University, 3232 SW Research Dr, Portland, OR, USA.
³Division of Structural Biology, BaobabAiBIO, 32, Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
⁴Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea.
⁵Department of Life Sciences, Pohang University of Science and Technology, 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk, Republic of Korea.
⁶Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
⁷Drug Information Research Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea.
⁸LigaChem Biosciences Inc, 10, Gukjegwahak 10-ro, Yuseong-gu, Daejeon, Republic of Korea.
⁹Research Institute of Molecular Alchemy, Gyeongsang National University, 501 Jinju-daero, Jinju-si, Republic of Korea.
¹⁰Institute for Bio-medical Convergence Science and Technology, Yonsei University, 03722, 50 Yonsei-ro, Seoul, Republic of Korea.
¹¹These authors contributed equally: Nienping Chang, Hoyoung Kim, Uijin Kim.
¹²These authors jointly supervised this work: Dongeun Yong, Hyun-Soo Cho.

Corresponding authors
Correspondence to Dongeun Yong or Hyun-Soo Cho.

Abstract

Anhydromuropeptide permease (AmpG) is a transporter protein located in the inner membrane of certain gram -negative bacteria, involved in peptidoglycan (PG) recycling and β-lactamase induction. Decreased AmpG function reduces resistance of antibiotic-resistant bacteria to β-lactam antibiotics. Therefore, AmpG-targeting inhibitors are promising ‘antibiotic adjuvants’. However, as the tertiary structure of AmpG has not yet been identified, the development of targeted inhibitors remains challenging. We present four cryo-electron microscopy (cryo-EM) structures: the apo-inward and apo-outward state structures and the inward-occluded and outward states complexed with the substrate GlcNAc-1,6-anhMurNAc. Through functional analysis and molecular dynamics (MD) simulations, we identified motif A, which stabilizes the outward state, substrate-binding pocket, and protonation-related residues. Based on the structure of AmpG and our experimental results, we propose a muropeptide transport mechanism for AmpG. A deeper understanding of its structure and transport mechanism provides a foundation for the development of antibiotic adjuvants.

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