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'''MtrF'''
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==Human Dopamine D3 Receptor==
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<Structure load='3PBL' size='500' frame='true' align='right' caption='Structure of the human dopamine D3 receptor in complex with eticlopride' scene='Insert optional scene name here' />
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==Introduction==
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Dopamine receptors are a class of metabotropic G protein-coupled receptors that are important in the central nervous system. Dopamine receptors are involved in many neurological processes that comprise motivation, pleasure, cognition, memory, learning, and fine motor skills. There are five subtype dopamine receptors, D1, D2, D3, D4, and D5. The D3 receptor is a part of the D2-like family.<ref>PMID:15148138</ref>
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== '''MtrF General Information''' ==
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==Function==
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Human dopamine D3 receptor is a protein that is encoded by the dopamine receptor gene (DRD3).<ref>PMID: 1916765</ref> The DRD3 gene codes for the D3 dopamine receptor that inhibits adenylyl cyclase through inhibitory G-proteins. G-protein coupled receptors are a family of transmembrane proteins that transmit chemical signals from outside the cell to cause changes inside of the cell. Adenylate cyclase is part of the G-protein receptor's signaling and catalyze the conversion of ATP to cyclic AMP (cAMP).<ref>Reece, Jane; Campbell, Neil (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5.</ref> The D3 receptor is located in the brain, suggesting that it plays a role in cognitive and emotional functions.<ref>National Center for Biotechnology Information, U.S. National Library of Medicine. DRD3 dopamine receptor D3 [Homo sapiens]. 19 November 2011.</ref> The human dopamine D3 receptor is membrane-bound and scattered in the cytoplasm. Receptor stimulation causes internalization of the receptors at the perinuclear areas. This is followed by the spreading of the receptors to the membrane. DRD3 is also contained in lipid rafts of renal proximal tubule cells.<ref>PMID: 19520868</ref>
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MtrF is a cell surface cytochrome that can play various roles in intermediating electron transfer straight to electron sinks, catalyzing electron exchange or partaking in extracellular intercytochrome electron exchange.(1) MtrF is a particular cell surface cytochrome on the bacteria known as Shewanella oneidensis. Certain bacterial species (Shewanella oneidensis) have the ability to utilize the extracellular mineral forms of Iron and Manganese as electron acceptors. This process requires three different proteins to move electrons across the cell membrane; this process ends in a decaheme cytochrome, mtrF, in Shewanella oneidensis.(2)
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==Structure==
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Human dopamine D3 receptor is 64% helical and 1% beta sheet. The protein is composed of 20 helices and 3 beta sheet strands. The helices are made up of 312 residues, and the beta sheets are made up of 9 residues. The entire protein consists of 481 residues.<ref name="structure">PMID: 21097933</ref> Dopamine D3 receptors are greatly expressed in the Islands of Calleja, a group of neural granule cells located within the ventral striatum in the brains of most animals, which is part of the limbic system. It is also found in the nucleus accumbens, a collection of neurons, and forms the main part of the ventral striatum.<ref>PMID:9473588</ref>
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== '''MtrF Structure''' ==
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==Ligands==
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Many non-selective prescription drugs bind to the D3 receptor. The binding of drugs either increases or inhibits the production of dopamine D3 receptors, which helps to diminish complications that are caused by certain diseases. Some agonists, agents that stimulate dopamine receptors, include:
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*Amphetamine<ref>Jones S, Kornblum JL, Kauer JA (August 2000). "Amphetamine blocks long-term synaptic depression in the ventral tegmental area". J. Neurosci. 20 (15): 5575–80. PMID 10908593. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10908593.</ref>
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*Methamphetamine<ref>Cruickshank, CC.; Dyer, KR. (Jul 2009). "A review of the clinical pharmacology of methamphetamine.". Addiction 104 (7): 1085–99. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289.</ref>
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Some antagonists, agents that inhibit dopamine receptors, include:
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*Clebopride<ref>Cuena Boy R, Maciá Martínez MA (1998). "[Extrapyramidal toxicity caused by metoclopramide and clebopride: study of voluntary notifications of adverse effects to the Spanish Drug Surveillance System]" (in Spanish). Atencion Primaria 21 (5): 289–95. PMID 9608114. Free full text</ref>
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*Nafadotride<ref>Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz JC, Everitt BJ, Sokoloff P. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 agonist. Nature. 1999;400:371–375.</ref>
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Two ligands that are associated with the dopamine D3 receptor are 3-chloro-5-ethyl-N{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-6-hydroxyl-2-methyloxybenzamide (<scene name='Sandbox_Reserved_383/Etq/1'>ETQ</scene>) and maltose (<scene name='Sandbox_Reserved_383/Mal/1'>MAL</scene>). ETQ binds to dopamine D3 receptor by Asp 110A and Phe346A. MAL binds by Asp 1020A, Glu 1022A, Glu1011A, and Leu1032A.<ref name="structure" />
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MtrF as mentioned above is a decaheme cytochrome, which means that there are ten heme groups that are spatially organized throughout the protein. Each heme is spread about 7A from its neighbor, this close space allows for speedy electron transfer. (5) The (ten) hemes are organized across four domains in a distinctive cross conformation, a staggered 65-? Octaheme chain intersects the protein and is bisected by a planar 45-? Tetraheme chain. All of the hemes in the MtrF crystal structure display bis-His axial ligand coordination. The His residue in the domains provide the distal ligands for the five hemes in the same domain. (5) Domains I and III contain antiparallel Beta-strands that connect two Greek key split Beta-barrel domains. (5) Domains II and IV bind five closely packed hemes covalently attached Cys residues to the motifs in each domain. (5) All the domains fold together so that the pentaheme domains II and IV are crowded together to form a central core with the two barrel domains I and III adjoining either side (5) The 3.2A crystal structure proposes that the hemes, each corresponding to two His ligands, are near enough for effective electron transfer. (2) Near-infrared magnetic circular dichroism and electron paramagnetic resonance spectroscopy provide additional support for these structural features. (2) The complete structure of MtrF is similar to an ellipsoid with dimensions of 85x70x30A. (5) This particular structure was able to provide molecular insight into how the reduction of insoluble substrates, soluble substrates, and cytochrome redox partners may be possible together at different termini on an electron transport chain on the cell surface. (1)
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==Diseases==
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Variations in the DRD3 gene is connected with essential tremor hereditary type 1 (ETM1).<ref name="disease">PMID: 16650084</ref>
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ETM1 is the most common movement disorder involving postural tremor of the arms, head, legs, body core, voice, jaw, and other facial muscles.
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This condition can be provoked by emotions, hunger, fatigue, and temperature extremes.<ref name="disease" />
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== '''MtrF’s role in Diseases''' ==
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==References==
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MtrF has been identified as a cell envelope protein that is involved with the resistance of hydrophobic antimicrobials in Neisseria Gonorrhoeae. MtrF is a protein that helps highlight the expression of detergent resistance by gonococci. MtrF is thought to act in accordance with the MtrC- MtrD- MtrE efflux pump; to make sure gonococci has high level resistance to specific hydrophobic agents. MtrF is located near the MtrR gene and is predicted to encode a cytoplasmic membrane protein that contains up to twelve transmembrane domains. The expression of MtrF is ultimately subject to MtrR’s transcriptional control. MtrF was given its name because it’s so closely tied to the protein MtrR. Several orthologues were discovered in a few Gram-negative and positive bacteria, indicating that perhaps the predicted products may represent an undescribed protein family that is highly involved with resistance of antimicrobials.(3)
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<references />
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== '''Regulation of MtrF''' ==
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A prime example of MtrF regulation is the study of Regulation of mtrF Expression in Neisseria Gonorrhoeae and Its Role in High-Level Antimicrobial Resistance. In this study the expression of MtrF was repressed by MtrR (the major repressor in the mtrCDE expression). Another repressor known as MpeR can also regulate the expression of MtrF. Repression of MtrF by MtrR and MpeR was used, demonstrating that the repressive effects mediated by these regulators are independent processes. MtrF was also disabled and the significant reduction in the induction of hydrophobic agent resistance and it was found that the expression of MtrF is enhanced when gonococci are grown under inducing conditions.(4)
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== '''References''' ==
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1.) Crystal structure of the outer membrane decaheme cytochrome MtrF. 3PMQ. Protein Data Bank. http://www.pdb.org/pdb/explore/explore.do?structureId=3PMQ. Accessed November 26,2011.
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2.) Clarke, Tom & Richardson, David. (20 Jun, 2011). Electron transport: Charting a heme conduit. Medica Journal.
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http://medicajournal.com/chemical-biology/our-choices-from-the-recent-literature.html. Accessed November 28, 2011.
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3.) Veal, Wendy L., & Shafer, William M. (28 Nov, 2002). Identification of a cell envelope protein (MtrF) involved in hydrophobic antimicrobial resistance in Neisseria gonorrhoeae.
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Journal of Antimicrobial Chemotherapy. http://jac.oxfordjournals.org/content/51/1/27.full. Accessed November 28, 2011.
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4.) Folster, Jason P., & Shafer, William M. (Jun 2005). Regulation of mtrF Expression in Neisseria Gonorrhoeae and Its Role in High-Level Antimicrobial Resistance. Journal of Bacteriology.
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http://jb.asm.org/content/187/11/3713.full. Accessed November 28, 2011.
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5.) Clarke, Thomas A., Edwards, Marcus A., Gates, Andrew J., Hall, Andrea, White, Gaye F., Bradley, Justin, Reardon, Catherine L., Shi, Liang, Beliaev, Alexander S., Marshall, Matthew J.,
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Wang, Zheming, Watmough, Nicholas J., Fredrickson, James K., Zachara, John M., Butt, Julea N., & Richardson, David J. (22 Nov, 2010). Structure of a bacterial cell surface decaheme electron conduit. PNAS. http://www.pnas.org/cgi/doi/10.1073/pnas.1017200108. Accessed November 28, 2011.
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Contents

Human Dopamine D3 Receptor

Structure of the human dopamine D3 receptor in complex with eticlopride

Drag the structure with the mouse to rotate

Introduction

Dopamine receptors are a class of metabotropic G protein-coupled receptors that are important in the central nervous system. Dopamine receptors are involved in many neurological processes that comprise motivation, pleasure, cognition, memory, learning, and fine motor skills. There are five subtype dopamine receptors, D1, D2, D3, D4, and D5. The D3 receptor is a part of the D2-like family.[1]

Function

Human dopamine D3 receptor is a protein that is encoded by the dopamine receptor gene (DRD3).[2] The DRD3 gene codes for the D3 dopamine receptor that inhibits adenylyl cyclase through inhibitory G-proteins. G-protein coupled receptors are a family of transmembrane proteins that transmit chemical signals from outside the cell to cause changes inside of the cell. Adenylate cyclase is part of the G-protein receptor's signaling and catalyze the conversion of ATP to cyclic AMP (cAMP).[3] The D3 receptor is located in the brain, suggesting that it plays a role in cognitive and emotional functions.[4] The human dopamine D3 receptor is membrane-bound and scattered in the cytoplasm. Receptor stimulation causes internalization of the receptors at the perinuclear areas. This is followed by the spreading of the receptors to the membrane. DRD3 is also contained in lipid rafts of renal proximal tubule cells.[5]

Structure

Human dopamine D3 receptor is 64% helical and 1% beta sheet. The protein is composed of 20 helices and 3 beta sheet strands. The helices are made up of 312 residues, and the beta sheets are made up of 9 residues. The entire protein consists of 481 residues.[6] Dopamine D3 receptors are greatly expressed in the Islands of Calleja, a group of neural granule cells located within the ventral striatum in the brains of most animals, which is part of the limbic system. It is also found in the nucleus accumbens, a collection of neurons, and forms the main part of the ventral striatum.[7]

Ligands

Many non-selective prescription drugs bind to the D3 receptor. The binding of drugs either increases or inhibits the production of dopamine D3 receptors, which helps to diminish complications that are caused by certain diseases. Some agonists, agents that stimulate dopamine receptors, include:

  • Amphetamine[8]
  • Methamphetamine[9]

Some antagonists, agents that inhibit dopamine receptors, include:

Two ligands that are associated with the dopamine D3 receptor are 3-chloro-5-ethyl-N{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-6-hydroxyl-2-methyloxybenzamide () and maltose (). ETQ binds to dopamine D3 receptor by Asp 110A and Phe346A. MAL binds by Asp 1020A, Glu 1022A, Glu1011A, and Leu1032A.[6]

Diseases

Variations in the DRD3 gene is connected with essential tremor hereditary type 1 (ETM1).[12] 

ETM1 is the most common movement disorder involving postural tremor of the arms, head, legs, body core, voice, jaw, and other facial muscles.
This condition can be provoked by emotions, hunger, fatigue, and temperature extremes.[12]

References

  1. ↑ Girault JA, Greengard P. The neurobiology of dopamine signaling. Arch Neurol. 2004 May;61(5):641-4. PMID:15148138 doi:10.1001/archneur.61.5.641
  2. ↑ Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, Schwartz JC, Berger R. Chromosomal localization of the human D3 dopamine receptor gene. Hum Genet. 1991 Sep;87(5):618-20. PMID:1916765
  3. ↑ Reece, Jane; Campbell, Neil (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5.
  4. ↑ National Center for Biotechnology Information, U.S. National Library of Medicine. DRD3 dopamine receptor D3 [Homo sapiens]. 19 November 2011.
  5. ↑ Villar VA, Jones JE, Armando I, Palmes-Saloma C, Yu P, Pascua AM, Keever L, Arnaldo FB, Wang Z, Luo Y, Felder RA, Jose PA. G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor. J Biol Chem. 2009 Aug 7;284(32):21425-34. Epub 2009 Jun 11. PMID:19520868 doi:10.1074/jbc.M109.003665
  6. ↑ 6.0 6.1 Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science. 2010 Nov 19;330(6007):1091-5. PMID:21097933 doi:10.1126/science.1197410
  7. ↑ Suzuki M, Hurd YL, Sokoloff P, Schwartz JC, Sedvall G. D3 dopamine receptor mRNA is widely expressed in the human brain. Brain Res. 1998 Jan 1;779(1-2):58-74. PMID:9473588
  8. ↑ Jones S, Kornblum JL, Kauer JA (August 2000). "Amphetamine blocks long-term synaptic depression in the ventral tegmental area". J. Neurosci. 20 (15): 5575–80. PMID 10908593. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10908593.
  9. ↑ Cruickshank, CC.; Dyer, KR. (Jul 2009). "A review of the clinical pharmacology of methamphetamine.". Addiction 104 (7): 1085–99. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289.
  10. ↑ Cuena Boy R, Maciá Martínez MA (1998). "[Extrapyramidal toxicity caused by metoclopramide and clebopride: study of voluntary notifications of adverse effects to the Spanish Drug Surveillance System]" (in Spanish). Atencion Primaria 21 (5): 289–95. PMID 9608114. Free full text
  11. ↑ Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz JC, Everitt BJ, Sokoloff P. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 agonist. Nature. 1999;400:371–375.
  12. ↑ 12.0 12.1 Lucotte G, Lagarde JP, Funalot B, Sokoloff P. Linkage with the Ser9Gly DRD3 polymorphism in essential tremor families. Clin Genet. 2006 May;69(5):437-40. PMID:16650084 doi:10.1111/j.1399-0004.2006.00600.x
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