6m0z: Difference between revisions

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'''Unreleased structure'''


The entry 6m0z is ON HOLD  until Mar 05 2022
==X-ray structure of Drosophila dopamine transporter with NET-like mutations (D121G/S426M/F471L) in L-norepinephrine bound form==
<StructureSection load='6m0z' size='340' side='right'caption='[[6m0z]], [[Resolution|resolution]] 2.88&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6m0z]] 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=6M0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6M0Z 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]] 2.88&#8491;</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=DMU:DECYL-BETA-D-MALTOPYRANOSIDE'>DMU</scene>, <scene name='pdbligand=LNR:L-NOREPINEPHRINE'>LNR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=6m0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m0z OCA], [https://pdbe.org/6m0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6m0z RCSB], [https://www.ebi.ac.uk/pdbsum/6m0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6m0z 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.


Authors: Shabareesh, P., Mallela, A.K., Joseph, D., Penmatsa, A.
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>


Description: X-ray structure of Drosophila dopamine transporter with NET-like mutations (D121G/S426M/F471L) in L-norepinephrine bound form
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Mallela, A.K]]
<div class="pdbe-citations 6m0z" style="background-color:#fffaf0;"></div>
[[Category: Shabareesh, P]]
== References ==
[[Category: Joseph, D]]
<references/>
[[Category: Penmatsa, A]]
__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 18:09, 29 November 2023

X-ray structure of Drosophila dopamine transporter with NET-like mutations (D121G/S426M/F471L) in L-norepinephrine bound formX-ray structure of Drosophila dopamine transporter with NET-like mutations (D121G/S426M/F471L) in L-norepinephrine bound form

Structural highlights

6m0z is a 3 chain structure with sequence from Drosophila melanogaster and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.88Å
Ligands:, , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).[1] [2] [3] [4] [5] [6]

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[7]

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

References

  1. ↑ Porzgen P, Park SK, Hirsh J, Sonders MS, Amara SG. The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines. Mol Pharmacol. 2001 Jan;59(1):83-95. doi: 10.1124/mol.59.1.83. PMID:11125028 doi:http://dx.doi.org/10.1124/mol.59.1.83
  2. ↑ Wu X, Gu HH. Cocaine affinity decreased by mutations of aromatic residue phenylalanine 105 in the transmembrane domain 2 of dopamine transporter. Mol Pharmacol. 2003 Mar;63(3):653-8. doi: 10.1124/mol.63.3.653. PMID:12606774 doi:http://dx.doi.org/10.1124/mol.63.3.653
  3. ↑ Kume K, Kume S, Park SK, Hirsh J, Jackson FR. Dopamine is a regulator of arousal in the fruit fly. J Neurosci. 2005 Aug 10;25(32):7377-84. doi: 10.1523/JNEUROSCI.2048-05.2005. PMID:16093388 doi:http://dx.doi.org/10.1523/JNEUROSCI.2048-05.2005
  4. ↑ Penmatsa A, Wang KH, Gouaux E. X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature. 2013 Sep 15. doi: 10.1038/nature12533. PMID:24037379 doi:10.1038/nature12533
  5. ↑ Ueno T, Kume K. Functional characterization of dopamine transporter in vivo using Drosophila melanogaster behavioral assays. Front Behav Neurosci. 2014 Sep 3;8:303. doi: 10.3389/fnbeh.2014.00303., eCollection 2014. PMID:25232310 doi:http://dx.doi.org/10.3389/fnbeh.2014.00303
  6. ↑ Wang KH, Penmatsa A, Gouaux E. Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature. 2015 May 21;521(7552):322-7. doi: 10.1038/nature14431. Epub 2015 May 11. PMID:25970245 doi:http://dx.doi.org/10.1038/nature14431
  7. ↑ Pidathala S, Mallela AK, Joseph D, Penmatsa A. Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters. Nat Commun. 2021 Apr 13;12(1):2199. PMID:33850134 doi:10.1038/s41467-021-22385-9

6m0z, resolution 2.88Å

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