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==CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)==
==CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)==
<StructureSection load='1hnn' size='340' side='right' caption='[[1hnn]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='1hnn' size='340' side='right'caption='[[1hnn]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1hnn]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HNN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1HNN FirstGlance]. <br>
<table><tr><td colspan='2'>[[1hnn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HNN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1HNN FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=SKF:1,2,3,4-TETRAHYDRO-ISOQUINOLINE-7-SULFONIC+ACID+AMIDE'>SKF</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PNMT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=SKF:1,2,3,4-TETRAHYDRO-ISOQUINOLINE-7-SULFONIC+ACID+AMIDE'>SKF</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phenylethanolamine_N-methyltransferase Phenylethanolamine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.28 2.1.1.28] </span></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=1hnn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hnn OCA], [https://pdbe.org/1hnn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1hnn RCSB], [https://www.ebi.ac.uk/pdbsum/1hnn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1hnn ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1hnn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hnn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1hnn RCSB], [http://www.ebi.ac.uk/pdbsum/1hnn PDBsum]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/PNMT_HUMAN PNMT_HUMAN]] Converts noradrenaline to adrenaline.  
[https://www.uniprot.org/uniprot/PNMT_HUMAN PNMT_HUMAN] Converts noradrenaline to adrenaline.
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hn/1hnn_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hn/1hnn_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </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/chain_selection.php?pdb_ID=2ata ConSurf].
</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=1hnn ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BACKGROUND: Adrenaline is localized to specific regions of the central nervous system (CNS), but its role therein is unclear because of a lack of suitable pharmacologic agents. Ideally, a chemical is required that crosses the blood-brain barrier, potently inhibits the adrenaline-synthesizing enzyme PNMT, and does not affect other catecholamine processes. Currently available PNMT inhibitors do not meet these criteria. We aim to produce potent, selective, and CNS-active PNMT inhibitors by structure-based design methods. The first step is the structure determination of PNMT. RESULTS: We have solved the crystal structure of human PNMT complexed with a cofactor product and a submicromolar inhibitor at a resolution of 2.4 A. The structure reveals a highly decorated methyltransferase fold, with an active site protected from solvent by an extensive cover formed from several discrete structural motifs. The structure of PNMT shows that the inhibitor interacts with the enzyme in a different mode from the (modeled) substrate noradrenaline. Specifically, the position and orientation of the amines is not equivalent. CONCLUSIONS: An unexpected finding is that the structure of PNMT provides independent evidence of both backward evolution and fold recruitment in the evolution of a complex enzyme from a simple fold. The proposed evolutionary pathway implies that adrenaline, the product of PNMT catalysis, is a relative newcomer in the catecholamine family. The PNMT structure reported here enables the design of potent and selective inhibitors with which to characterize the role of adrenaline in the CNS. Such chemical probes could potentially be useful as novel therapeutics.
Getting the adrenaline going: crystal structure of the adrenaline-synthesizing enzyme PNMT.,Martin JL, Begun J, McLeish MJ, Caine JM, Grunewald GL Structure. 2001 Oct;9(10):977-85. PMID:11591352<ref>PMID:11591352</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


==See Also==
==See Also==
*[[Phenylethanolamine N-methyltransferase|Phenylethanolamine N-methyltransferase]]
*[[Phenylethanolamine N-methyltransferase|Phenylethanolamine N-methyltransferase]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Phenylethanolamine N-methyltransferase]]
[[Category: Large Structures]]
[[Category: Begun, J]]
[[Category: Begun J]]
[[Category: Caine, J M]]
[[Category: Caine JM]]
[[Category: Grunewald, G L]]
[[Category: Grunewald GL]]
[[Category: Martin, J L]]
[[Category: Martin JL]]
[[Category: McLeish, M J]]
[[Category: McLeish MJ]]
[[Category: Adrenaline synthesis]]
[[Category: Methyltransferase]]
[[Category: S-adenosyl methionine]]
[[Category: Transferase]]

Latest revision as of 10:28, 7 February 2024

CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)

Structural highlights

1hnn is a 2 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:X-ray diffraction, Resolution 2.4Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PNMT_HUMAN Converts noradrenaline to adrenaline.

Evolutionary Conservation

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

See Also

1hnn, resolution 2.40Å

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