The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors

Abstract The gastric proton pump H+,K+-ATPase acidifies the gastric lumen, and thus its inhibitors, including the imidazo[1,2-a]pyridine class of K+-competitive acid blockers (P-CABs), have potential application as acid-suppressing drugs. We determined the electron crystallographic structure of H+,K...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Kazuhiro Abe, Jun Shimokawa, Mao Naito, Keith Munson, Olga Vagin, George Sachs, Hiroshi Suzuki, Kazutoshi Tani, Yoshinori Fujiyoshi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1de29038e09d4db7b9fd269cc769e0cd
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1de29038e09d4db7b9fd269cc769e0cd
record_format	dspace
spelling	oai:doaj.org-article:1de29038e09d4db7b9fd269cc769e0cd2021-12-02T11:52:34ZThe cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors10.1038/s41598-017-06698-82045-2322https://doaj.org/article/1de29038e09d4db7b9fd269cc769e0cd2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06698-8https://doaj.org/toc/2045-2322Abstract The gastric proton pump H+,K+-ATPase acidifies the gastric lumen, and thus its inhibitors, including the imidazo[1,2-a]pyridine class of K+-competitive acid blockers (P-CABs), have potential application as acid-suppressing drugs. We determined the electron crystallographic structure of H+,K+-ATPase at 6.5 Å resolution in the E2P state with bound BYK99, a potent P-CAB with a restricted ring structure. The BYK99 bound structure has an almost identical profile to that of a previously determined structure with bound SCH28080, the original P-CAB prototype, but is significantly different from the previously reported P-CAB-free form, illustrating a common conformational change is required for P-CAB binding. The shared conformational changes include a distinct movement of transmembrane helix 2 (M2), from its position in the previously reported P-CAB-free form, to a location proximal to the P-CAB binding site in the present BYK99-bound structure. Site-specific mutagenesis within M2 revealed that D137 and N138, which face the P-CAB binding site in our model, significantly affect the inhibition constant (K i) of P-CABs. We also found that A335 is likely to be near the bridging nitrogen at the restricted ring structure of the BYK99 inhibitor. These provide clues to elucidate the binding site parameters and mechanism of P-CAB inhibition of gastric acid secretion.Kazuhiro AbeJun ShimokawaMao NaitoKeith MunsonOlga VaginGeorge SachsHiroshi SuzukiKazutoshi TaniYoshinori FujiyoshiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kazuhiro Abe Jun Shimokawa Mao Naito Keith Munson Olga Vagin George Sachs Hiroshi Suzuki Kazutoshi Tani Yoshinori Fujiyoshi The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors
description	Abstract The gastric proton pump H+,K+-ATPase acidifies the gastric lumen, and thus its inhibitors, including the imidazo[1,2-a]pyridine class of K+-competitive acid blockers (P-CABs), have potential application as acid-suppressing drugs. We determined the electron crystallographic structure of H+,K+-ATPase at 6.5 Å resolution in the E2P state with bound BYK99, a potent P-CAB with a restricted ring structure. The BYK99 bound structure has an almost identical profile to that of a previously determined structure with bound SCH28080, the original P-CAB prototype, but is significantly different from the previously reported P-CAB-free form, illustrating a common conformational change is required for P-CAB binding. The shared conformational changes include a distinct movement of transmembrane helix 2 (M2), from its position in the previously reported P-CAB-free form, to a location proximal to the P-CAB binding site in the present BYK99-bound structure. Site-specific mutagenesis within M2 revealed that D137 and N138, which face the P-CAB binding site in our model, significantly affect the inhibition constant (K i) of P-CABs. We also found that A335 is likely to be near the bridging nitrogen at the restricted ring structure of the BYK99 inhibitor. These provide clues to elucidate the binding site parameters and mechanism of P-CAB inhibition of gastric acid secretion.
format	article
author	Kazuhiro Abe Jun Shimokawa Mao Naito Keith Munson Olga Vagin George Sachs Hiroshi Suzuki Kazutoshi Tani Yoshinori Fujiyoshi
author_facet	Kazuhiro Abe Jun Shimokawa Mao Naito Keith Munson Olga Vagin George Sachs Hiroshi Suzuki Kazutoshi Tani Yoshinori Fujiyoshi
author_sort	Kazuhiro Abe
title	The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors
title_short	The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors
title_full	The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors
title_fullStr	The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors
title_full_unstemmed	The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors
title_sort	cryo-em structure of gastric h+,k+-atpase with bound byk99, a high-affinity member of k+-competitive, imidazo[1,2-a]pyridine inhibitors
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1de29038e09d4db7b9fd269cc769e0cd
work_keys_str_mv	AT kazuhiroabe thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT junshimokawa thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT maonaito thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT keithmunson thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT olgavagin thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT georgesachs thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT hiroshisuzuki thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT kazutoshitani thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT yoshinorifujiyoshi thecryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT kazuhiroabe cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT junshimokawa cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT maonaito cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT keithmunson cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT olgavagin cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT georgesachs cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT hiroshisuzuki cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT kazutoshitani cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors AT yoshinorifujiyoshi cryoemstructureofgastrichkatpasewithboundbyk99ahighaffinitymemberofkcompetitiveimidazo12apyridineinhibitors
_version_	1718394969967820800

The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors

Ejemplares similares