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2xfu

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Revision as of 08:16, 17 October 2018

Human monoamine oxidase B with tranylcypromine

Structural highlights

2xfu is a 2 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 1ojb. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	2c67, 1s3e, 2c73, 2v60, 1oj9, 2vz2, 1ojd, 1s3b, 2c66, 2xfo, 2bk5, 1h8r, 2c70, 2xfn, 2bk3, 2c76, 2vrl, 1oja, 2v5z, 2byb, 2vrm, 2c65, 2xcg, 2c64, 2xfp, 2bk4, 2c75, 2v61, 1s2y, 2c72, 1gos, 1s2q, 2xfq, 1ojc
Gene:	MAOB (HUMAN)
Activity:	Monoamine oxidase, with EC number 1.4.3.4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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

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

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^[1]

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

References

↑ Bonivento D, Milczek EM, McDonald GR, Binda C, Holt A, Edmondson DE, Mattevi A. Potentiation of ligand binding through cooperative effects in monoamine oxidase B. J Biol Chem. 2010 Sep 20. PMID:20855894 doi:10.1074/jbc.M110.169482

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/2xfu"

@@ Line 1: / Line 1: @@
-==human monoamine oxidase B with tranylcypromine==
+==Human monoamine oxidase B with tranylcypromine==
 <StructureSection load='2xfu' size='340' side='right' caption='[[2xfu]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<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>
 <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='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='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>
@@ Line 23: / Line 24: @@
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-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.
+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.
-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>
+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>
@@ Line 37: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Monoamine oxidase]]
 [[Category: Binda, C]]

2xfu

From Proteopedia

Revision as of 08:16, 17 October 2018

Human monoamine oxidase B with tranylcypromine

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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