9JRM

outward-open hSLC19A1 + 2'3'-CDAS

9JRM の概要

• エントリーDOI: 10.2210/pdb9jrm/pdb
• EMDBエントリー: 61760
• 分子名称: Soluble cytochrome b562,Reduced folate transporter,Soluble cytochrome b562,Reduced folate transporter,fusion protein, (1~{R},3~{S},6~{R},8~{R},9~{R},10~{S},12~{S},15~{R},17~{R},18~{R})-8,17-bis(6-aminopurin-9-yl)-3,12-bis(oxidanylidene)-3,12-bis(sulfanyl)-2,4,7,11,13,16-hexaoxa-3$l^{5},12$l^{5}-diphosphatricyclo[13.2.1.0^{6,10}]octadecane-9,18-diol (2 entities in total)
• 機能のキーワード: outward-open hslc19a1, membrane protein
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 78210.50

構造登録者

Zhang, Q.X.,Liu, K.X.,Gao, P. (登録日: 2024-09-29, 公開日: 2025-02-26, 最終更新日: 2025-04-23)

主引用文献

Zhang, Q.,Zhang, X.,Liu, K.,Zhu, Y.,Nie, X.,Ma, J.,Sun, P.,Li, Z.,Gao, Y.,Liu, S.,Gao, A.,Zhang, L.,Gao, P.
Molecular basis of SLC19A1-mediated folate and cyclic dinucleotide transport.
Nat Commun, 16:3146-3146, 2025

PubMed Abstract: The solute carrier protein SLC19A1 is crucial for transporting folate nutrients, antifolate chemotherapeutics, and more recently cyclic dinucleotides (CDNs) immune transmitters, influencing various physiological and pathological processes. While the inward-open state of human SLC19A1 (hSLC19A1) has been previously described, key aspects regarding its conformational dynamics, substrate selectivity, and precise mechanisms underlying CDNs transport remain elusive. Using an antibody-facilitated conformation screening strategy, we present cryo-electron microscopy structures of hSLC19A1 in its outward-open state with and without bound substrates, revealing detailed mechanisms of substrate recognition and conformational changes during transport. We identify both general and specific features for folate/antifolate recognition, including an SLC19A1-specific pocket for accommodating γ-carboxylate-modified antifolates. Intriguingly, CDNs bind as monomers within the canonical pocket of outward-open hSLC19A1, contrasting with dimeric binding in inward-open structures. Together with functional assays, these findings provide a framework for developing antifolate drugs and CDN-targeted therapies, advancing our understanding of SLC19A1's physiological and therapeutic functions.

PubMed: 40175380
DOI: 10.1038/s41467-025-58378-1

実験手法

ELECTRON MICROSCOPY (3.34 Å)