8z7z

From Proteopedia

(Difference between revisions)

Current revision

SLC19A2-Thiamine inward structure

Structural highlights

8z7z is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.23Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

S19A2_HUMAN Thiamine-responsive megaloblastic anemia syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

S19A2_HUMAN High-affinity transporter for the intake of thiamine (PubMed:10391222, PubMed:10542220, PubMed:21836059, PubMed:33008889, PubMed:35512554, PubMed:35724964). Mediates H(+)-dependent pyridoxine transport (PubMed:33008889, PubMed:35512554, PubMed:35724964).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine transporters SLC19A2 and SLC19A3 primarily regulate cellular uptake of both vitamins. Genetic mutations in these transporters, which cause thiamine and pyridoxine deficiency, have been implicated in severe neurometabolic diseases. Additionally, various prescribed medicines, including metformin and fedratinib, manipulate thiamine transporters, complicating the therapeutic effect. Despite their physiological and pharmacological significance, the molecular underpinnings of substrate and drug recognition remain unknown. Here we present ten cryo-EM structures of human thiamine transporters SLC19A3 and SLC19A2 in outward- and inward-facing conformations, complexed with thiamine, pyridoxine, metformin, fedratinib, and amprolium. These structural insights, combined with functional characterizations, illuminate the translocation mechanism of diverse chemical entities, and enhance our understanding of drug-nutrient interactions mediated by thiamine transporters.

Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3.,Li P, Zhu Z, Wang Y, Zhang X, Yang C, Zhu Y, Zhou Z, Chao Y, Long Y, Gao Y, Liu S, Zhang L, Gao P, Qu Q Nat Commun. 2024 Dec 30;15(1):10924. doi: 10.1038/s41467-024-55359-8. PMID:39738067^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet. 1999 Jul;22(3):305-8. PMID:10391222 doi:10.1038/10379
↑ Dutta B, Huang W, Molero M, Kekuda R, Leibach FH, Devoe LD, Ganapathy V, Prasad PD. Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem. 1999 Nov 5;274(45):31925-9. PMID:10542220 doi:10.1074/jbc.274.45.31925
↑ Nabokina SM, Senthilkumar SR, Said HM. Tspan-1 interacts with the thiamine transporter-1 in human intestinal epithelial cells and modulates its stability. Am J Physiol Gastrointest Liver Physiol. 2011 Nov;301(5):G808-13. PMID:21836059 doi:10.1152/ajpgi.00269.2011
↑ Yamashiro T, Yasujima T, Said HM, Yuasa H. pH-dependent pyridoxine transport by SLC19A2 and SLC19A3: Implications for absorption in acidic microclimates. J Biol Chem. 2020 Dec 11;295(50):16998-17008. PMID:33008889 doi:10.1074/jbc.RA120.013610
↑ Yamashiro T, Yasujima T, Yuasa H. Animal species differences in the pyridoxine transport function of SLC19A3: Absence of Slc19a3-mediated pyridoxine uptake in the rat small intestine. Drug Metab Pharmacokinet. 2022 Jun;44:100456. PMID:35512554 doi:10.1016/j.dmpk.2022.100456
↑ Miyake K, Yasujima T, Takahashi S, Yamashiro T, Yuasa H. Identification of the amino acid residues involved in the species-dependent differences in the pyridoxine transport function of SLC19A3. J Biol Chem. 2022 Aug;298(8):102161. PMID:35724964 doi:10.1016/j.jbc.2022.102161
↑ Li P, Zhu Z, Wang Y, Zhang X, Yang C, Zhu Y, Zhou Z, Chao Y, Long Y, Gao Y, Liu S, Zhang L, Gao P, Qu Q. Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3. Nat Commun. 2024 Dec 30;15(1):10924. PMID:39738067 doi:10.1038/s41467-024-55359-8

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8z7z"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8z7z is ON HOLD  until 2026-04-21
+==SLC19A2-Thiamine inward structure==
+<StructureSection load='8z7z' size='340' side='right'caption='[[8z7z]], [[Resolution|resolution]] 3.23&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8z7z]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8Z7Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8Z7Z FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.23&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VIB:3-(4-AMINO-2-METHYL-PYRIMIDIN-5-YLMETHYL)-5-(2-HYDROXY-ETHYL)-4-METHYL-THIAZOL-3-IUM'>VIB</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8z7z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8z7z OCA], [https://pdbe.org/8z7z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8z7z RCSB], [https://www.ebi.ac.uk/pdbsum/8z7z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8z7z ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/S19A2_HUMAN S19A2_HUMAN] Thiamine-responsive megaloblastic anemia syndrome. The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/S19A2_HUMAN S19A2_HUMAN] High-affinity transporter for the intake of thiamine (PubMed:10391222, PubMed:10542220, PubMed:21836059, PubMed:33008889, PubMed:35512554, PubMed:35724964). Mediates H(+)-dependent pyridoxine transport (PubMed:33008889, PubMed:35512554, PubMed:35724964).<ref>PMID:10391222</ref> <ref>PMID:10542220</ref> <ref>PMID:21836059</ref> <ref>PMID:33008889</ref> <ref>PMID:35512554</ref> <ref>PMID:35724964</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine transporters SLC19A2 and SLC19A3 primarily regulate cellular uptake of both vitamins. Genetic mutations in these transporters, which cause thiamine and pyridoxine deficiency, have been implicated in severe neurometabolic diseases. Additionally, various prescribed medicines, including metformin and fedratinib, manipulate thiamine transporters, complicating the therapeutic effect. Despite their physiological and pharmacological significance, the molecular underpinnings of substrate and drug recognition remain unknown. Here we present ten cryo-EM structures of human thiamine transporters SLC19A3 and SLC19A2 in outward- and inward-facing conformations, complexed with thiamine, pyridoxine, metformin, fedratinib, and amprolium. These structural insights, combined with functional characterizations, illuminate the translocation mechanism of diverse chemical entities, and enhance our understanding of drug-nutrient interactions mediated by thiamine transporters.
-Authors:
+Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3.,Li P, Zhu Z, Wang Y, Zhang X, Yang C, Zhu Y, Zhou Z, Chao Y, Long Y, Gao Y, Liu S, Zhang L, Gao P, Qu Q Nat Commun. 2024 Dec 30;15(1):10924. doi: 10.1038/s41467-024-55359-8. PMID:39738067<ref>PMID:39738067</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8z7z" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Gao P]]
+[[Category: Li PP]]
+[[Category: Qu QH]]
+[[Category: Wang Y]]
+[[Category: Zhu ZN]]

8z7z

From Proteopedia

Current revision

SLC19A2-Thiamine inward structure

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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