8IJV

Cryo-EM structure of the gastric proton pump with bound DQ-02

Summary for 8IJV

• Entry DOI: 10.2210/pdb8ijv/pdb
• EMDB information: 35500
• Descriptor: Sodium/potassium-transporting ATPase subunit alpha, Potassium-transporting ATPase subunit beta, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (8 entities in total)
• Functional Keywords: p-type atpase, p2-type atpase, membrane protein
• Biological source: Sus scrofa (pig); More
• Total number of polymer chains: 2
• Total formula weight: 153170.47

Authors

Abe, K.,Yokoshima, S.,Yoshimori, A. (deposition date: 2023-02-28, release date: 2023-08-30, Last modification date: 2024-10-09)

Primary citation

Abe, K.,Ozako, M.,Inukai, M.,Matsuyuki, Y.,Kitayama, S.,Kanai, C.,Nagai, C.,Gopalasingam, C.C.,Gerle, C.,Shigematsu, H.,Umekubo, N.,Yokoshima, S.,Yoshimori, A.
Deep learning driven de novo drug design based on gastric proton pump structures.
Commun Biol, 6:956-956, 2023

PubMed Abstract: Existing drugs often suffer in their effectiveness due to detrimental side effects, low binding affinity or pharmacokinetic problems. This may be overcome by the development of distinct compounds. Here, we exploit the rich structural basis of drug-bound gastric proton pump to develop compounds with strong inhibitory potency, employing a combinatorial approach utilizing deep generative models for de novo drug design with organic synthesis and cryo-EM structural analysis. Candidate compounds that satisfy pharmacophores defined in the drug-bound proton pump structures, were designed in silico utilizing our deep generative models, a workflow termed Deep Quartet. Several candidates were synthesized and screened according to their inhibition potencies in vitro, and their binding poses were in turn identified by cryo-EM. Structures reaching up to 2.10 Å resolution allowed us to evaluate and re-design compound structures, heralding the most potent compound in this study, DQ-18 (N-methyl-4-((2-(benzyloxy)-5-chlorobenzyl)oxy)benzylamine), which shows a K value of 47.6 nM. Further high-resolution cryo-EM analysis at 2.08 Å resolution unambiguously determined the DQ-18 binding pose. Our integrated approach offers a framework for structure-based de novo drug development based on the desired pharmacophores within the protein structure.

PubMed: 37726448
DOI: 10.1038/s42003-023-05334-8

Experimental method

ELECTRON MICROSCOPY (2.1 Å)