2xfu

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==human monoamine oxidase B with tranylcypromine==
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==Human monoamine oxidase B with tranylcypromine==
<StructureSection load='2xfu' size='340' side='right' caption='[[2xfu]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
<StructureSection load='2xfu' size='340' side='right' caption='[[2xfu]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[2xfu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1ojb 1ojb]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XFU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XFU FirstGlance]. <br>
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<table><tr><td colspan='2'>[[2xfu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1ojb 1ojb]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XFU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XFU FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3PL:3-PHENYLPROPANAL'>3PL</scene>, <scene name='pdbligand=FA8:[[(2R,3S,4S)-5-[(4AS)-7,8-DIMETHYL-2,4-DIOXO-4A,5-DIHYDROBENZO[G]PTERIDIN-10-YL]-2,3,4-TRIHYDROXY-PENTOXY]-HYDROXY-PHOSPHORYL]+[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL+HYDROGEN+PHOSPHATE'>FA8</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3PL:3-PHENYLPROPANAL'>3PL</scene>, <scene name='pdbligand=FA8:[[(2R,3S,4S)-5-[(4AS)-7,8-DIMETHYL-2,4-DIOXO-4A,5-DIHYDROBENZO[G]PTERIDIN-10-YL]-2,3,4-TRIHYDROXY-PENTOXY]-HYDROXY-PHOSPHORYL]+[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL+HYDROGEN+PHOSPHATE'>FA8</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2c67|2c67]], [[1s3e|1s3e]], [[2c73|2c73]], [[2v60|2v60]], [[1oj9|1oj9]], [[2vz2|2vz2]], [[1ojd|1ojd]], [[1s3b|1s3b]], [[2c66|2c66]], [[2xfo|2xfo]], [[2bk5|2bk5]], [[1h8r|1h8r]], [[2c70|2c70]], [[2xfn|2xfn]], [[2bk3|2bk3]], [[2c76|2c76]], [[2vrl|2vrl]], [[1oja|1oja]], [[2v5z|2v5z]], [[2byb|2byb]], [[2vrm|2vrm]], [[2c65|2c65]], [[2xcg|2xcg]], [[2c64|2c64]], [[2xfp|2xfp]], [[2bk4|2bk4]], [[2c75|2c75]], [[2v61|2v61]], [[1s2y|1s2y]], [[2c72|2c72]], [[1gos|1gos]], [[1s2q|1s2q]], [[2xfq|2xfq]], [[1ojc|1ojc]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2c67|2c67]], [[1s3e|1s3e]], [[2c73|2c73]], [[2v60|2v60]], [[1oj9|1oj9]], [[2vz2|2vz2]], [[1ojd|1ojd]], [[1s3b|1s3b]], [[2c66|2c66]], [[2xfo|2xfo]], [[2bk5|2bk5]], [[1h8r|1h8r]], [[2c70|2c70]], [[2xfn|2xfn]], [[2bk3|2bk3]], [[2c76|2c76]], [[2vrl|2vrl]], [[1oja|1oja]], [[2v5z|2v5z]], [[2byb|2byb]], [[2vrm|2vrm]], [[2c65|2c65]], [[2xcg|2xcg]], [[2c64|2c64]], [[2xfp|2xfp]], [[2bk4|2bk4]], [[2c75|2c75]], [[2v61|2v61]], [[1s2y|1s2y]], [[2c72|2c72]], [[1gos|1gos]], [[1s2q|1s2q]], [[2xfq|2xfq]], [[1ojc|1ojc]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAOB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Monoamine_oxidase Monoamine oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.4.3.4 1.4.3.4] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Monoamine_oxidase Monoamine oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.4.3.4 1.4.3.4] </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=2xfu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xfu OCA], [http://pdbe.org/2xfu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xfu RCSB], [http://www.ebi.ac.uk/pdbsum/2xfu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xfu 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=2xfu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xfu OCA], [http://pdbe.org/2xfu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xfu RCSB], [http://www.ebi.ac.uk/pdbsum/2xfu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xfu ProSAT]</span></td></tr>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound enzyme that catalyzes the oxidative deamination of arylalkylamine neurotransmitters and has been a target for a number of clinically used drug inhibitors. The 1.7-A structure of the reversible isatin-MAO-B complex has been determined; it forms a basis for the interpretation of the enzyme's structure when bound to either reversible or irreversible inhibitors. 1,4-Diphenyl-2-butene is found to be a reversible MAO-B inhibitor, which occupies both the entrance and substrate cavity space in the enzyme. Comparison of these two structures identifies Ile-199 as a "gate" between the two cavities. Rotation of the side chain allows for either separation or fusion of the two cavities. Inhibition of the enzyme with N-(2-aminoethyl)-p-chlorobenzamide results in the formation of a covalent N(5) flavin adduct with the phenyl ring of the inhibitor occupying a position in the catalytic site overlapping that of isatin. Inhibition of MAO-B with the clinically used trans-2-phenylcyclopropylamine results in the formation of a covalent C(4a) flavin adduct with an opened cyclopropyl ring and the phenyl ring in a parallel orientation to the flavin. The peptide bond between the flavin-substituted Cys-397 and Tyr-398 is in a cis conformation, which allows the proper orientation of the phenolic ring of Tyr-398 in the active site. The flavin ring exists in a twisted nonplanar conformation, which is observed in the oxidized form as well as in both the N(5) and the C(4a) adducts. An immobile water molecule is H-bonded to Lys-296 and to the N(5) of the flavin as observed in other flavin-dependent amine oxidases. The active site cavities are highly apolar; however, hydrophilic areas exist near the flavin and direct the amine moiety of the substrate for binding and catalysis. Small conformational changes are observed on comparison of the different inhibitor-enzyme complexes. Future MAO-B drug design will need to consider "induced fit" contributions as an element in ligand-enzyme interactions.
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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.
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Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures.,Binda C, Li M, Hubalek F, Restelli N, Edmondson DE, Mattevi A Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9750-5. Epub 2003 Aug 11. PMID:12913124<ref>PMID:12913124</ref>
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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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Human]]
[[Category: Monoamine oxidase]]
[[Category: Monoamine oxidase]]
[[Category: Binda, C]]
[[Category: Binda, C]]

Revision as of 08:16, 17 October 2018

Human monoamine oxidase B with tranylcypromine

2xfu, resolution 2.20Å

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