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2cl5

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Catechol-O-methyltransferase in complex with an inhibitor

Structural highlights

2cl5 is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

COMT_RAT Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.

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

In this work, we present a comparative case study of "ortho-" and "meta-nitrated" catecholic inhibitors of catechol-O-methyltransferase (COMT), with regard to their interaction with the catalytic site of the enzyme and the in vitro regioselective formation of their mono-O-methyl ether metabolites. In particular, the effects of altering the attachment position of the inhibitors' side-chain substituent, within the classic nitrocatechol pharmacophore, were investigated. For this purpose, we compared two simple regioisomeric nitrocatechol-type inhibitors of COMT, BIA 3-228 and BIA 8-176, which contain the benzoyl substituent attached at the meta and ortho positions, respectively, relative to the nitro group. The two compounds were slowly O-methylated by COMT in vitro, but the particular substitution pattern of each compound was shown to have a profound impact on the regioselectivity of their O-methylation. To provide a plausible interpretation of these results, a comprehensive analysis of the protein-inhibitor interactions and of the relative chemical susceptibility to O-methylation of the catechol hydroxyl groups was performed by means of docking simulations and ab initio molecular orbital calculations. The major structural and chemical factors that determine the enzyme regioselectivity of O-methylation were identified, and the X-ray structure of the complex of COMT with S-adenosyl-l-methionine and BIA 8-176 is herein disclosed. This is the first reported structure of the soluble form of COMT complexed with a nitrocatecholic inhibitor having a bulky substituent group in adjacent position (ortho) to the nitro group. Structural and dynamic aspects of this complex are analyzed and discussed, in the context of the present study.

Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: interactions with the active site and regioselectivity of O-methylation.,Palma PN, Rodrigues ML, Archer M, Bonifacio MJ, Loureiro AI, Learmonth DA, Carrondo MA, Soares-da-Silva P Mol Pharmacol. 2006 Jul;70(1):143-53. Epub 2006 Apr 17. PMID:16618795^[1]

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

References

↑ Palma PN, Rodrigues ML, Archer M, Bonifacio MJ, Loureiro AI, Learmonth DA, Carrondo MA, Soares-da-Silva P. Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: interactions with the active site and regioselectivity of O-methylation. Mol Pharmacol. 2006 Jul;70(1):143-53. Epub 2006 Apr 17. PMID:16618795 doi:10.1124/mol.106.023119

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2cl5"

@@ Line 3: / Line 3: @@
 <StructureSection load='2cl5' size='340' side='right'caption='[[2cl5]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2cl5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CL5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CL5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2cl5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CL5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CL5 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BIE:(3,4-DIHYDROXY-2-NITROPHENYL)(PHENYL)METHANONE'>BIE</scene>, <scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</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]] 1.6&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Catechol_O-methyltransferase Catechol O-methyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.6 2.1.1.6] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BIE:(3,4-DIHYDROXY-2-NITROPHENYL)(PHENYL)METHANONE'>BIE</scene>, <scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</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=2cl5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cl5 OCA], [https://pdbe.org/2cl5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cl5 RCSB], [https://www.ebi.ac.uk/pdbsum/2cl5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cl5 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/COMT_RAT COMT_RAT]] Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
+[https://www.uniprot.org/uniprot/COMT_RAT COMT_RAT] Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 36: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: Buffalo rat]]
-[[Category: Catechol O-methyltransferase]]
 [[Category: Large Structures]]
-[[Category: Archer, M]]
+[[Category: Rattus norvegicus]]
-[[Category: Bonifacio, M J]]
+[[Category: Archer M]]
-[[Category: Carrondo, M A]]
+[[Category: Bonifacio MJ]]
-[[Category: Learmonth, D A]]
+[[Category: Carrondo MA]]
-[[Category: Loureiro, A I]]
+[[Category: Learmonth DA]]
-[[Category: Palma, P N]]
+[[Category: Loureiro AI]]
-[[Category: Rodrigues, M L]]
+[[Category: Palma PN]]
-[[Category: Soares-Da-Silva, P]]
+[[Category: Rodrigues ML]]
-[[Category: Alternative initiation]]
+[[Category: Soares-Da-Silva P]]
-[[Category: Catechol-o-methyltransferase]]
-[[Category: Catecholamine metabolism]]
-[[Category: Comt inhibitor]]
-[[Category: Magnesium]]
-[[Category: Membrane]]
-[[Category: Metal-binding]]
-[[Category: Methyltransferase]]
-[[Category: Neurotransmitter degradation]]
-[[Category: Phosphorylation]]
-[[Category: Signal-anchor]]
-[[Category: Transferase]]
-[[Category: Transmembrane]]

2cl5

From Proteopedia

Current revision

Catechol-O-methyltransferase in complex with an inhibitor

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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