7W48

Crystal structure of the gastric proton pump complexed with PF-03716556

PDB DOI: https://doi.org/10.2210/pdb7W48/pdb

Classification: HYDROLASE
Organism(s): Sus scrofa
Expression System: Homo sapiens
Mutation(s): Yes
Membrane Protein: Yes OPMPDBTMMemProtMDmpstruc

Deposited: 2021-11-26 Released: 2022-01-05
Deposition Author(s): Abe, K., Tanaka, S.
Funding Organization(s): Japan Society for the Promotion of Science (JSPS)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.50 ?
R-Value Free: 0.306
R-Value Work: 0.252
R-Value Observed: 0.255

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump.

Tanaka, S., Morita, M., Yamagishi, T., Madapally, H.V., Hayashida, K., Khandelia, H., Gerle, C., Shigematsu, H., Oshima, A., Abe, K.

(2022) J Med Chem 65: 7843-7853

PubMed: 35604136 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.2c00338
Primary Citation of Related Structures:
7W47, 7W48, 7W49, 7W4A

PubMed Abstract:
As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K ⁺-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 ?. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases.

Organizational Affiliation

Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, 464-8601, Japan.

Macromolecule Content

Total Structure Weight: 150.77 kDa
Atom Count: 9,916
Modelled Residue Count: 1,248
Deposited Residue Count: 1,324
Unique protein chains: 2

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Potassium-transporting ATPase alpha chain 1	A	1,034	Sus scrofa	Mutation(s): 3 Gene Names: ATP4A EC: 3.6.3.10 (PDB Primary Data), 7.2.2.19 (UniProt) Membrane Entity: Yes
UniProt
Find proteins for P19156 (Sus scrofa) Explore P19156 Go to UniProtKB: P19156
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P19156
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Potassium-transporting ATPase subunit beta	B	290	Sus scrofa	Mutation(s): 0 Gene Names: ATP4B Membrane Entity: Yes
UniProt
Find proteins for P18434 (Sus scrofa) Explore P18434 Go to UniProtKB: P18434
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P18434
Glycosylation
Glycosylation Sites: 3	Glycosylation Focus chain B
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
PCW Query on PCW Download Ideal Coordinates CCD File SDF format, chain M [auth B] MOL2 format, chain M [auth B] mmCIF format, chain M [auth B]	M [auth B]	1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE C₄₄ H₈₅ N O₈ P SNKAWJBJQDLSFF-NVKMUCNASA-O		Interactions Focus chain M [auth B] Interactions & Density Focus chain M [auth B]
CE1 Query on CE1 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain H [auth A] MOL2 format, chain D [auth A] MOL2 format, chain H [auth A] mmCIF format, chain D [auth A] mmCIF format, chain H [auth A]	D [auth A], H [auth A]	O-DODECANYL OCTAETHYLENE GLYCOL C₂₈ H₅₈ O₉ YYELLDKEOUKVIQ-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain H [auth A] Interactions & Density Focus chain D [auth A] Focus chain H [auth A]
8BZ (Subject of Investigation/LOI) Query on 8BZ Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A] mmCIF format, chain I [auth A]	I [auth A]	N-(2-hydroxyethyl)-N,2-dimethyl-8-[[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino]imidazo[1,2-a]pyridine-6-carboxamide C₂₂ H₂₆ N₄ O₃ YBHKBMJREUZHOV-QGZVFWFLSA-N		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain J [auth B] SDF format, chain K [auth B] SDF format, chain L [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B]	J [auth B], K [auth B], L [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Interactions & Density Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B]
RB Query on RB Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A]	E [auth A], F [auth A], G [auth A]	RUBIDIUM ION Rb NCCSSGKUIKYAJD-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]