한빛사
>
한빛사논문
한빛사논문
- 조회320
Nat. Chem. Biol., Feb 28 2024, | https://doi.org/10.1038/s41589-024-01559-8
Antiviral drug recognition and elevator-type transport motions of CNT3
Nicholas J. Wright 1, Feng Zhang1, Yang Suo1, Lingyang Kong2, Ying Yin1, Justin G. Fedor1, Kedar Sharma 3, Mario J. Borgnia 3, Wonpil Im 2 & Seok-Yong Lee1
1Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.
2Departments of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, PA, USA.
3Department of Health and Human Services, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA.
Corresponding author : Correspondence to Seok-Yong Lee.
Abstract
Nucleoside analogs have broad clinical utility as antiviral drugs. Key to their systemic distribution and cellular entry are human nucleoside transporters. Here, we establish that the human concentrative nucleoside transporter 3 (CNT3) interacts with antiviral drugs used in the treatment of coronavirus infections. We report high-resolution single-particle cryo-electron microscopy structures of bovine CNT3 complexed with antiviral nucleosides N
4-hydroxycytidine, PSI-6206, GS-441524 and ribavirin, all in inward-facing states. Notably, we found that the orally bioavailable antiviral molnupiravir arrests CNT3 in four distinct conformations, allowing us to capture cryo-electron microscopy structures of drug-loaded outward-facing and drug-loaded intermediate states. Our studies uncover the conformational trajectory of CNT3 during membrane transport of a nucleoside analog antiviral drug, yield new insights into the role of interactions between the transport and the scaffold domains in elevator-like domain movements during drug translocation, and provide insights into the design of nucleoside analog antiviral prodrugs with improved oral bioavailability.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-03-12)
- 국외 연구진
- 생명과학 > 생화학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
