6m0f: Difference between revisions
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==X-ray structure of Drosophila dopamine transporter with subsiteB mutations (D121G/S426M) in substrate-free form== | |||
<StructureSection load='6m0f' size='340' side='right'caption='[[6m0f]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6m0f]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6M0F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6M0F FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=P4G:1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE'>P4G</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=6m0f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m0f OCA], [https://pdbe.org/6m0f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6m0f RCSB], [https://www.ebi.ac.uk/pdbsum/6m0f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6m0f ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DAT_DROME DAT_DROME] Sodium-dependent dopamine transporter which terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:11125028, PubMed:12606774, PubMed:24037379, PubMed:25970245). Also transports tyramine and norepinephrine, shows less efficient transport of octopamine and does not transport serotonin (PubMed:11125028, PubMed:12606774). Plays a role in the regulation of the rest/activity cycle (PubMed:16093388, PubMed:25232310).<ref>PMID:11125028</ref> <ref>PMID:12606774</ref> <ref>PMID:16093388</ref> <ref>PMID:24037379</ref> <ref>PMID:25232310</ref> <ref>PMID:25970245</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Norepinephrine is a biogenic amine neurotransmitter that has widespread effects on alertness, arousal and pain sensation. Consequently, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ the Drosophila melanogaster dopamine transporter as a surrogate for the norepinephrine transporter and determine X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters. | |||
Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters.,Pidathala S, Mallela AK, Joseph D, Penmatsa A Nat Commun. 2021 Apr 13;12(1):2199. doi: 10.1038/s41467-021-22385-9. PMID:33850134<ref>PMID:33850134</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6m0f" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Drosophila melanogaster]] | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Joseph D]] | |||
[[Category: Mallela AK]] | |||
[[Category: Penmatsa A]] | |||
[[Category: Shabareesh P]] | |||
Latest revision as of 18:08, 29 November 2023
X-ray structure of Drosophila dopamine transporter with subsiteB mutations (D121G/S426M) in substrate-free formX-ray structure of Drosophila dopamine transporter with subsiteB mutations (D121G/S426M) in substrate-free form
Structural highlights
FunctionDAT_DROME Sodium-dependent dopamine transporter which terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:11125028, PubMed:12606774, PubMed:24037379, PubMed:25970245). Also transports tyramine and norepinephrine, shows less efficient transport of octopamine and does not transport serotonin (PubMed:11125028, PubMed:12606774). Plays a role in the regulation of the rest/activity cycle (PubMed:16093388, PubMed:25232310).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedNorepinephrine is a biogenic amine neurotransmitter that has widespread effects on alertness, arousal and pain sensation. Consequently, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ the Drosophila melanogaster dopamine transporter as a surrogate for the norepinephrine transporter and determine X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters. Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters.,Pidathala S, Mallela AK, Joseph D, Penmatsa A Nat Commun. 2021 Apr 13;12(1):2199. doi: 10.1038/s41467-021-22385-9. PMID:33850134[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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