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7jsj

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Structure of the NaCT-PF2 complex

Structural highlights

7jsj is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	SLC13A5, NACT (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[S13A5_HUMAN] Undetermined early-onset epileptic encephalopathy;Amelocerebrohypohidrotic syndrome;Pyridoxine-dependent epilepsy. The disease is caused by variants affecting the gene represented in this entry.

Function

[S13A5_HUMAN] High-affinity sodium/citrate cotransporter that mediates citrate entry into cells. The transport process is electrogenic; it is the trivalent form of citrate rather than the divalent form that is recognized as a substrate. May facilitate the utilization of circulating citrate for the generation of metabolic energy and for the synthesis of fatty acids and cholesterol.^[1] ^[2]

Publication Abstract from PubMed

Citrate is best known as an intermediate in the tricarboxylic acid cycle of the cell. In addition to this essential role in energy metabolism, the tricarboxylate anion also acts as both a precursor and a regulator of fatty acid synthesis(1-3). Thus, the rate of fatty acid synthesis correlates directly with the cytosolic concentration of citrate(4,5). Liver cells import citrate through the sodium-dependent citrate transporter NaCT (encoded by SLC13A5) and, as a consequence, this protein is a potential target for anti-obesity drugs. Here, to understand the structural basis of its inhibition mechanism, we determined cryo-electron microscopy structures of human NaCT in complexes with citrate or a small-molecule inhibitor. These structures reveal how the inhibitor-which binds to the same site as citrate-arrests the transport cycle of NaCT. The NaCT-inhibitor structure also explains why the compound selectively inhibits NaCT over two homologous human dicarboxylate transporters, and suggests ways to further improve the affinity and selectivity. Finally, the NaCT structures provide a framework for understanding how various mutations abolish the transport activity of NaCT in the brain and thereby cause epilepsy associated with mutations in SLC13A5 in newborns (which is known as SLC13A5-epilepsy)(6-8).

Structure and inhibition mechanism of the human citrate transporter NaCT.,Sauer DB, Song J, Wang B, Hilton JK, Karpowich NK, Mindell JA, Rice WJ, Wang DN Nature. 2021 Feb 17. pii: 10.1038/s41586-021-03230-x. doi:, 10.1038/s41586-021-03230-x. PMID:33597751^[3]

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

References

↑ Inoue K, Zhuang L, Ganapathy V. Human Na+ -coupled citrate transporter: primary structure, genomic organization, and transport function. Biochem Biophys Res Commun. 2002 Dec 6;299(3):465-71. doi:, 10.1016/s0006-291x(02)02669-4. PMID:12445824 doi:http://dx.doi.org/10.1016/s0006-291x(02)02669-4
↑ Hardies K, de Kovel CG, Weckhuysen S, Asselbergh B, Geuens T, Deconinck T, Azmi A, May P, Brilstra E, Becker F, Barisic N, Craiu D, Braun KP, Lal D, Thiele H, Schubert J, Weber Y, van 't Slot R, Nurnberg P, Balling R, Timmerman V, Lerche H, Maudsley S, Helbig I, Suls A, Koeleman BP, De Jonghe P. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain. 2015 Nov;138(Pt 11):3238-50. doi: 10.1093/brain/awv263. Epub 2015 Sep 17. PMID:26384929 doi:http://dx.doi.org/10.1093/brain/awv263
↑ Sauer DB, Song J, Wang B, Hilton JK, Karpowich NK, Mindell JA, Rice WJ, Wang DN. Structure and inhibition mechanism of the human citrate transporter NaCT. Nature. 2021 Feb 17. pii: 10.1038/s41586-021-03230-x. doi:, 10.1038/s41586-021-03230-x. PMID:33597751 doi:http://dx.doi.org/10.1038/s41586-021-03230-x

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/7jsj"

@@ Line 3: / Line 3: @@
 <StructureSection load='7jsj' size='340' side='right'caption='[[7jsj]], [[Resolution|resolution]] 3.12&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7jsj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JSJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JSJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7jsj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JSJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JSJ FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=X3M:(2R)-2-[2-(4-tert-butylphenyl)ethyl]-2-hydroxybutanedioic+acid'>X3M</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SLC13A5, NACT ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=7jsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jsj OCA], [https://pdbe.org/7jsj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jsj RCSB], [https://www.ebi.ac.uk/pdbsum/7jsj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jsj ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Rice, W J]]

7jsj

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Current revision

Structure of the NaCT-PF2 complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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