9W4K
Cryo-EM structure of inhibitor E822-1968 bound human urea transporter A2.
This is a non-PDB format compatible entry.
Summary for 9W4K
| Entry DOI | 10.2210/pdb9w4k/pdb |
| EMDB information | 65636 |
| Descriptor | Urea transporter 2, 3-(3-methoxyphenyl)-~{N}-[(3-methoxyphenyl)methyl]-1~{H}-pyrazole-5-carboxamide (2 entities in total) |
| Functional Keywords | urea transporter, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 131271.48 |
| Authors | |
| Primary citation | Liu, L.,Li, Z.,Zhang, C.,Zhang, Y.,Huang, Z.,Zhang, D.,Li, D.,Zhao, J.,Miao, Y.,Cai, B.,Zhu, K.,Sun, J.P.,Hou, G.,Sun, Y.,Yang, B.,Yu, X.,Huang, S. Hotspot pocket-based discovery of urea transporter selective inhibitors. Nat Commun, 17:-, 2026 Cited by PubMed Abstract: Urea transporter (UT) inhibitors are a promising class of diuretics, as selective inhibitors targeting UT-A subtypes have demonstrated considerable therapeutic potential. Herein, we employ a two-round progressive hotspot pocket-based virtual screening approach combined with biological validation to identify M353-0039 as a highly potent and selective inhibitor of UT-A2. We conduct cryo-electron microscopy to solve the structures of UT-A2 bound with the two inhibitors, M353-0039 and E822-1968, at the resolution of 2.7 Å and 2.9 Å respectively, and elucidate the structural mechanism underlying the superior efficacy and selectivity of M353-0039. Compared with the inhibitor HQA2 and E822-1968, M353-0039 occupies a deeper binding pocket and forms more interactions with UT-A2, thus leading to greater inhibitory potency. We demonstrate that the selectivity of M353-0039 is driven by the nonconserved residues C285 and G322 within the "T-T" subpocket of UT-A2. Finally, we validate the selective effects of M353-0039 in inhibiting UT-A2 function both in mouse models and hepatic cell. These findings not only identify a selective inhibitor as a tool that can be applied to elucidate the unique physiological roles of UT-A2 but also provide an available method for efficiently developing UT-A-selective inhibitors with potent activity as the next-generation diuretics. PubMed: 42009654DOI: 10.1038/s41467-026-71834-w PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.9 Å) |
Structure validation
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