5YLV

Crystal structure of the gastric proton pump complexed with SCH28080

PDB DOI: https://doi.org/10.2210/pdb5YLV/pdb

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

Deposited: 2017-10-19 Released: 2018-04-11
Deposition Author(s): Abe, K., Irie, K., Nakanishi, H., Fujiyoshi, Y.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.80 Å
R-Value Free: 0.292
R-Value Work: 0.240
R-Value Observed: 0.242

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Crystal structures of the gastric proton pump

Abe, K., Irie, K., Nakanishi, H., Suzuki, H., Fujiyoshi, Y.

(2018) Nature 556: 214-218

PubMed: 29618813 Search on PubMed
DOI: https://doi.org/10.1038/s41586-018-0003-8
Primary Citation of Related Structures:
5YLU, 5YLV

PubMed Abstract:
The gastric proton pump-the H ⁺, K ⁺-ATPase-is a P-type ATPase responsible for acidifying the gastric juice down to pH 1. This corresponds to a million-fold proton gradient across the membrane of the parietal cell, the steepest known cation gradient of any mammalian tissue. The H ⁺, K ⁺-ATPase is an important target for drugs that treat gastric acid-related diseases. Here we present crystal structures of the H ⁺, K ⁺-ATPase in complex with two blockers, vonoprazan and SCH28080, in the luminal-open state, at 2.8 Å resolution. The drugs have partially overlapping but clearly distinct binding modes in the middle of a conduit running from the gastric lumen to the cation-binding site. The crystal structures suggest that the tight configuration at the cation-binding site lowers the pK _a value of Glu820 sufficiently to enable the release of a proton even into the pH 1 environment of the stomach.

Organizational Affiliation

Cellular and Structural Physiology Institute, Nagoya University, Nagoya, Japan. kabe@cespi.nagoya-u.ac.jp.

Macromolecule Content

Total Structure Weight: 150.53 kDa
Atom Count: 9,937
Modelled Residue Count: 1,248
Deposited Residue Count: 1,323
Unique protein chains: 2

Macromolecules

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(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 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	289	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
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 L [auth B] MOL2 format, chain L [auth B]	L [auth B]	1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE C₄₄ H₈₅ N O₈ P SNKAWJBJQDLSFF-NVKMUCNASA-O		Interactions Focus chain L [auth B] Interactions & Density Focus chain L [auth B]
CE1 Query on CE1 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain M [auth B] MOL2 format, chain E [auth A] MOL2 format, chain M [auth B]	E [auth A], M [auth B]	O-DODECANYL OCTAETHYLENE GLYCOL C₂₈ H₅₈ O₉ YYELLDKEOUKVIQ-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain M [auth B] Interactions & Density Focus chain E [auth A] Focus chain M [auth B]
8WX Query on 8WX Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	2-(2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridin-3-yl)ethanenitrile C₁₇ H₁₅ N₃ O PYKJFEPAUKAXNN-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B]	I [auth B], J [auth B], K [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Interactions & Density Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B]
RB Query on RB Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A]	F [auth A], G [auth A], H [auth A]	RUBIDIUM ION Rb NCCSSGKUIKYAJD-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A]	D [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
BFD Query on BFD	A	L-PEPTIDE LINKING	C₄ H₆ Be F₃ N O₄		ASP

Binding Affinity Annotations
ID	Source	Binding Affinity
8WX	BindingDB: 5YLV	IC50: min: 65, max: 1590 (nM) from 3 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.80 Å
R-Value Free: 0.292
R-Value Work: 0.240
R-Value Observed: 0.242
Space Group: P 3₁ 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 105.05	α = 90
b = 105.05	β = 90
c = 368.54	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data reduction
XDS	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2018-04-11

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2018-04-11
Type: Initial release
Version 1.1: 2018-04-18
Changes: Data collection, Database references
Version 1.2: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Data collection, Derived calculations, Structure summary
Version 1.3: 2023-11-22
Changes: Data collection, Database references, Refinement description, Structure summary