7lql: Difference between revisions
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==Crystal structure of the R375D mutant of LeuT== | ==Crystal structure of the R375D mutant of LeuT== | ||
<StructureSection load='7lql' size='340' side='right'caption='[[7lql]]' scene=''> | <StructureSection load='7lql' size='340' side='right'caption='[[7lql]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LQL FirstGlance]. <br> | <table><tr><td colspan='2'>[[7lql]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Aquae Aquae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LQL FirstGlance]. <br> | ||
</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=7lql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lql OCA], [https://pdbe.org/7lql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lql RCSB], [https://www.ebi.ac.uk/pdbsum/7lql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lql ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALA:ALANINE'>ALA</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6w95|6w95]], [[6w99|6w99]]</div></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">snf, aq_2077 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=224324 AQUAE])</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=7lql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lql OCA], [https://pdbe.org/7lql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lql RCSB], [https://www.ebi.ac.uk/pdbsum/7lql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lql ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD. | |||
Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia.,Aguilar JI, Cheng MH, Font J, Schwartz AC, Ledwitch K, Duran A, Mabry SJ, Belovich AN, Zhu Y, Carter AM, Shi L, Kurian MA, Fenollar-Ferrer C, Meiler J, Ryan RM, Mchaourab HS, Bahar I, Matthies HJ, Galli A Elife. 2021 May 18;10. pii: 68039. doi: 10.7554/eLife.68039. PMID:34002696<ref>PMID:34002696</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7lql" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Aquae]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Aguilar J]] | [[Category: Aguilar, J]] | ||
[[Category: Font J]] | [[Category: Font, J]] | ||
[[Category: Galli A]] | [[Category: Galli, A]] | ||
[[Category: Ryan R]] | [[Category: Ryan, R]] | ||
[[Category: Leucine transporter]] | |||
[[Category: Transport protein]] | |||
[[Category: Transporter]] | |||