7zha

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Structure of human OCT3 in complex with inhibitor decynium-22Structure of human OCT3 in complex with inhibitor decynium-22

Structural highlights

7zha 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 3.55Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

S22A3_HUMAN Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:10196521, PubMed:10966924, PubMed:12538837, PubMed:17460754, PubMed:20858707). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:10966924). Functions as a Na(+)- and Cl(-)-independent, bidirectional uniporter (PubMed:12538837). Implicated in monoamine neurotransmitters uptake such as dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, histamine, serotonin and tyramine, thereby supporting a role in homeostatic regulation of aminergic neurotransmission in the brain (PubMed:10196521, PubMed:16581093, PubMed:20858707). Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with low efficiency (PubMed:17460754). May be involved in the uptake and disposition of cationic compounds by renal clearance from the blood flow (PubMed:10966924). May contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable). Mediates the transport of polyamine spermidine and putrescine (By similarity). Mediates the bidirectional transport of polyamine agmatine (PubMed:12538837). Also transports guanidine (PubMed:10966924). May also mediate intracellular transport of organic cations, thereby playing a role in amine metabolism and intracellular signaling (By similarity).[UniProtKB:O88446][1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 A resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms.

Structural basis of organic cation transporter-3 inhibition.,Khanppnavar B, Maier J, Herborg F, Gradisch R, Lazzarin E, Luethi D, Yang JW, Qi C, Holy M, Jantsch K, Kudlacek O, Schicker K, Werge T, Gether U, Stockner T, Korkhov VM, Sitte HH Nat Commun. 2022 Nov 7;13(1):6714. doi: 10.1038/s41467-022-34284-8. PMID:36344565[8]

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

See Also

References

  1. ↑ Grundemann D, Schechinger B, Rappold GA, Schomig E. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci. 1998 Sep;1(5):349-51. doi: 10.1038/1557. PMID:10196521 doi:http://dx.doi.org/10.1038/1557
  2. ↑ Wu X, Huang W, Ganapathy ME, Wang H, Kekuda R, Conway SJ, Leibach FH, Ganapathy V. Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney. Am J Physiol Renal Physiol. 2000 Sep;279(3):F449-58. PMID:10966924
  3. ↑ Gründemann D, Hahne C, Berkels R, Schömig E. Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2). J Pharmacol Exp Ther. 2003 Feb;304(2):810-7. PMID:12538837 doi:10.1124/jpet.102.044404
  4. ↑ Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52. PMID:16581093 doi:10.1016/j.neuropharm.2006.01.005
  5. ↑ Taubert D, Grimberg G, Stenzel W, Schömig E. Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons. PLoS One. 2007 Apr 25;2(4):e385. PMID:17460754 doi:10.1371/journal.pone.0000385
  6. ↑ Duan H, Wang J. Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. PMID:20858707 doi:10.1124/jpet.110.170142
  7. ↑ Hau RK, Klein RR, Wright SH, Cherrington NJ. Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier. Drug Metab Dispos. 2022 Jun;50(6):770-780. PMID:35307651 doi:10.1124/dmd.121.000748
  8. ↑ Khanppnavar B, Maier J, Herborg F, Gradisch R, Lazzarin E, Luethi D, Yang JW, Qi C, Holy M, Jäntsch K, Kudlacek O, Schicker K, Werge T, Gether U, Stockner T, Korkhov VM, Sitte HH. Structural basis of organic cation transporter-3 inhibition. Nat Commun. 2022 Nov 7;13(1):6714. PMID:36344565 doi:10.1038/s41467-022-34284-8

7zha, resolution 3.55Å

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