1l0c: Difference between revisions

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[[Image:1l0c.png|left|200px]]


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==Investigation of the Roles of Catalytic Residues in Serotonin N-Acetyltransferase==
The line below this paragraph, containing "STRUCTURE_1l0c", creates the "Structure Box" on the page.
<StructureSection load='1l0c' size='340' side='right'caption='[[1l0c]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[1l0c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Ovis_aries Ovis aries]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1L0C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1L0C FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=COT:COA-S-ACETYL+TRYPTAMINE'>COT</scene></td></tr>
{{STRUCTURE_1l0c|  PDB=1l0c  |  SCENE=  }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1l0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1l0c OCA], [https://pdbe.org/1l0c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1l0c RCSB], [https://www.ebi.ac.uk/pdbsum/1l0c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1l0c ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SNAT_SHEEP SNAT_SHEEP] Controls the night/day rhythm of melatonin production in the pineal gland. Catalyzes the N-acetylation of serotonin into N-acetylserotonin, the penultimate step in the synthesis of melatonin.<ref>PMID:15644438</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/l0/1l0c_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1l0c ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase (AANAT)) is a critical enzyme in the light-mediated regulation of melatonin production and circadian rhythm. It is a member of the GNAT (GCN-5-related N-acetyltransferase) superfamily of enzymes, which catalyze a diverse array of biologically important acetyl transfer reactions from antibiotic resistance to chromatin remodeling. In this study, we probed the functional properties of two histidines (His-120 and His-122) and a tyrosine (Tyr-168) postulated to be important in the mechanism of AANAT based on prior x-ray structural and biochemical studies. Using a combination of steady-state kinetic measurements of microviscosity effects and pH dependence on the H122Q, H120Q, and H120Q/H122Q AANAT mutants, we show that His-122 (with an apparent pK(a) of 7.3) contributes approximately 6-fold to the acetyltransferase chemical step as either a remote catalytic base or hydrogen bond donor. Furthermore, His-120 and His-122 appear to contribute redundantly to this function. By analysis of the Y168F AANAT mutant, it was demonstrated that Tyr-168 contributes approximately 150-fold to the acetyltransferase chemical step and is responsible for the basic limb of the pH-rate profile with an apparent (subnormal) pK(a) of 8.5. Paradoxically, Y168F AANAT showed 10-fold enhanced apparent affinity for acetyl-CoA despite the loss of a hydrogen bond between the Tyr phenol and the CoA sulfur atom. The X-ray crystal structure of Y168F AANAT bound to a bisubstrate analog inhibitor showed no significant structural perturbation of the enzyme compared with the wild-type complex, but revealed the loss of dual inhibitor conformations present in the wild-type complex. Taken together with kinetic measurements, these crystallographic studies allow us to propose the relevant structural conformations related to the distinct alkyltransferase and acetyltransferase reactions catalyzed by AANAT. These findings have significant implications for understanding GNAT catalysis and the design of potent and selective inhibitors.


===Investigation of the Roles of Catalytic Residues in Serotonin N-Acetyltransferase===
Investigation of the roles of catalytic residues in serotonin N-acetyltransferase.,Scheibner KA, De Angelis J, Burley SK, Cole PA J Biol Chem. 2002 May 17;277(20):18118-26. Epub 2002 Mar 7. PMID:11884405<ref>PMID:11884405</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1l0c" style="background-color:#fffaf0;"></div>


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==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_11884405}}, adds the Publication Abstract to the page
*[[Serotonin N-acetyltransferase|Serotonin N-acetyltransferase]]
(as it appears on PubMed at http://www.pubmed.gov), where 11884405 is the PubMed ID number.
== References ==
-->
<references/>
{{ABSTRACT_PUBMED_11884405}}
__TOC__
 
</StructureSection>
==About this Structure==
[[Category: Large Structures]]
[[1l0c]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Ovis_aries Ovis aries]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1L0C OCA].
 
==Reference==
<ref group="xtra">PMID:011884405</ref><references group="xtra"/>
[[Category: Aralkylamine N-acetyltransferase]]
[[Category: Ovis aries]]
[[Category: Ovis aries]]
[[Category: Angelis, J De.]]
[[Category: Burley SK]]
[[Category: Burley, S K.]]
[[Category: Cole PA]]
[[Category: Cole, P A.]]
[[Category: De Angelis J]]
[[Category: Scheibner, K A.]]
[[Category: Scheibner KA]]
[[Category: Alternate conformation]]
[[Category: Bisubstrate analog]]
[[Category: Enzyme-inhibitor complex]]
[[Category: Transferase]]

Latest revision as of 12:08, 16 August 2023

Investigation of the Roles of Catalytic Residues in Serotonin N-AcetyltransferaseInvestigation of the Roles of Catalytic Residues in Serotonin N-Acetyltransferase

Structural highlights

1l0c is a 1 chain structure with sequence from Ovis aries. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SNAT_SHEEP Controls the night/day rhythm of melatonin production in the pineal gland. Catalyzes the N-acetylation of serotonin into N-acetylserotonin, the penultimate step in the synthesis of melatonin.[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase (AANAT)) is a critical enzyme in the light-mediated regulation of melatonin production and circadian rhythm. It is a member of the GNAT (GCN-5-related N-acetyltransferase) superfamily of enzymes, which catalyze a diverse array of biologically important acetyl transfer reactions from antibiotic resistance to chromatin remodeling. In this study, we probed the functional properties of two histidines (His-120 and His-122) and a tyrosine (Tyr-168) postulated to be important in the mechanism of AANAT based on prior x-ray structural and biochemical studies. Using a combination of steady-state kinetic measurements of microviscosity effects and pH dependence on the H122Q, H120Q, and H120Q/H122Q AANAT mutants, we show that His-122 (with an apparent pK(a) of 7.3) contributes approximately 6-fold to the acetyltransferase chemical step as either a remote catalytic base or hydrogen bond donor. Furthermore, His-120 and His-122 appear to contribute redundantly to this function. By analysis of the Y168F AANAT mutant, it was demonstrated that Tyr-168 contributes approximately 150-fold to the acetyltransferase chemical step and is responsible for the basic limb of the pH-rate profile with an apparent (subnormal) pK(a) of 8.5. Paradoxically, Y168F AANAT showed 10-fold enhanced apparent affinity for acetyl-CoA despite the loss of a hydrogen bond between the Tyr phenol and the CoA sulfur atom. The X-ray crystal structure of Y168F AANAT bound to a bisubstrate analog inhibitor showed no significant structural perturbation of the enzyme compared with the wild-type complex, but revealed the loss of dual inhibitor conformations present in the wild-type complex. Taken together with kinetic measurements, these crystallographic studies allow us to propose the relevant structural conformations related to the distinct alkyltransferase and acetyltransferase reactions catalyzed by AANAT. These findings have significant implications for understanding GNAT catalysis and the design of potent and selective inhibitors.

Investigation of the roles of catalytic residues in serotonin N-acetyltransferase.,Scheibner KA, De Angelis J, Burley SK, Cole PA J Biol Chem. 2002 May 17;277(20):18118-26. Epub 2002 Mar 7. PMID:11884405[2]

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

See Also

References

  1. Ganguly S, Weller JL, Ho A, Chemineau P, Malpaux B, Klein DC. Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205. Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1222-7. Epub 2005 Jan 11. PMID:15644438 doi:0406871102
  2. Scheibner KA, De Angelis J, Burley SK, Cole PA. Investigation of the roles of catalytic residues in serotonin N-acetyltransferase. J Biol Chem. 2002 May 17;277(20):18118-26. Epub 2002 Mar 7. PMID:11884405 doi:10.1074/jbc.M200595200

1l0c, resolution 2.30Å

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