2xfn: Difference between revisions
New page: '''Unreleased structure''' The entry 2xfn is ON HOLD Authors: Bonivento, D., Milczek, E.M., McDonald, G.R., Binda, C., Holt, A., Edmondson, D.E., Mattevi, A. Description: human monoami... |
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==Human monoamine oxidase B in complex with 2-(2-benzofuranyl)-2- imidazoline== | |||
<StructureSection load='2xfn' size='340' side='right'caption='[[2xfn]], [[Resolution|resolution]] 1.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2xfn]] 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=2XFN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XFN FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C15:N-DODECYL-N,N-DIMETHYL-3-AMMONIO-1-PROPANESULFONATE'>C15</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=XCG:2-(2-BENZOFURANYL)-2-IMIDAZOLINE'>XCG</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=2xfn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xfn OCA], [https://pdbe.org/2xfn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xfn RCSB], [https://www.ebi.ac.uk/pdbsum/2xfn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xfn ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/AOFB_HUMAN AOFB_HUMAN] Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine. | |||
== 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/xf/2xfn_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=2xfn ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Crystallographic and biochemical studies have been employed to identify the binding site and mechanism for potentiation of imidazoline-binding in human monoamine oxidase B (MAO B). 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) inhibits recombinant human MAO B with a Ki of 8.3+/-0.6 muM whereas tranylcypromine-inhibited MAO B binds 2-BFI with a Kd of 9+/-2 nM, representing an increase in binding energy Delta(DeltaG) of -3.9 kcal/mol. Crystal structures show the imidazoline ligand bound in a site that is distinct from the substrate-binding cavity. Contributions to account for the increase in binding affinity upon tranylcypromine inhibition include a conformational change in the side chain of Gln206 and a "closed conformation" of the side chain of Ile199, forming a hydrophobic "sandwich" with the side chain of Ile316 on each face of the benzofuran ring of 2-BFI. Data with the Ile199Ala mutant of human MAO B and failure to observe a similar binding potentiation with rat MAO B, where Ile316 is replaced with a Val residue, support an allosteric mechanism where the increased binding affinity of 2-BFI results from a cooperative increase in H-bond strength through formation of a more hydrophobic milieu. These insights should prove valuable in the design of high affinity and specific reversible MAO B inhibitors. | |||
Potentiation of ligand binding through cooperative effects in monoamine oxidase B.,Bonivento D, Milczek EM, McDonald GR, Binda C, Holt A, Edmondson DE, Mattevi A J Biol Chem. 2010 Sep 20. PMID:20855894<ref>PMID:20855894</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2xfn" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Monoamine oxidase|Monoamine oxidase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Binda C]] | |||
[[Category: Bonivento D]] | |||
[[Category: Edmondson DE]] | |||
[[Category: Holt A]] | |||
[[Category: Mattevi A]] | |||
[[Category: McDonald GR]] | |||
[[Category: Milczek EM]] | |||
Latest revision as of 13:30, 20 December 2023
Human monoamine oxidase B in complex with 2-(2-benzofuranyl)-2- imidazolineHuman monoamine oxidase B in complex with 2-(2-benzofuranyl)-2- imidazoline
Structural highlights
FunctionAOFB_HUMAN Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine. 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 PubMedCrystallographic and biochemical studies have been employed to identify the binding site and mechanism for potentiation of imidazoline-binding in human monoamine oxidase B (MAO B). 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) inhibits recombinant human MAO B with a Ki of 8.3+/-0.6 muM whereas tranylcypromine-inhibited MAO B binds 2-BFI with a Kd of 9+/-2 nM, representing an increase in binding energy Delta(DeltaG) of -3.9 kcal/mol. Crystal structures show the imidazoline ligand bound in a site that is distinct from the substrate-binding cavity. Contributions to account for the increase in binding affinity upon tranylcypromine inhibition include a conformational change in the side chain of Gln206 and a "closed conformation" of the side chain of Ile199, forming a hydrophobic "sandwich" with the side chain of Ile316 on each face of the benzofuran ring of 2-BFI. Data with the Ile199Ala mutant of human MAO B and failure to observe a similar binding potentiation with rat MAO B, where Ile316 is replaced with a Val residue, support an allosteric mechanism where the increased binding affinity of 2-BFI results from a cooperative increase in H-bond strength through formation of a more hydrophobic milieu. These insights should prove valuable in the design of high affinity and specific reversible MAO B inhibitors. Potentiation of ligand binding through cooperative effects in monoamine oxidase B.,Bonivento D, Milczek EM, McDonald GR, Binda C, Holt A, Edmondson DE, Mattevi A J Biol Chem. 2010 Sep 20. PMID:20855894[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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