7zw3: Difference between revisions
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==Crystal Structure of human MAO B in complex with (Z)-N-benzyl-1-(8-hydroxyquinolin-2-yl)methanimine oxide (inhibitor 19)== | |||
<StructureSection load='7zw3' size='340' side='right'caption='[[7zw3]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7zw3]] 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=7ZW3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZW3 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]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AI0:1-(8-oxidanylquinolin-2-yl)-~{N}-(phenylmethyl)methanimine+oxide'>AI0</scene>, <scene name='pdbligand=C15:N-DODECYL-N,N-DIMETHYL-3-AMMONIO-1-PROPANESULFONATE'>C15</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</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=7zw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zw3 OCA], [https://pdbe.org/7zw3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zw3 RCSB], [https://www.ebi.ac.uk/pdbsum/7zw3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zw3 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC(50) = 1.06 +/- 0.31 nmol/L) and hMAO-B (IC(50) = 4.46 +/- 0.18 mumol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1deltaE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19. | |||
8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.,Knez D, Diez-Iriepa D, Chioua M, Gottinger A, Denic M, Chantegreil F, Nachon F, Brazzolotto X, Skrzypczak-Wiercioch A, Meden A, Pislar A, Kos J, Zakelj S, Stojan J, Salat K, Serrano J, Fernandez AP, Sanchez-Garcia A, Martinez-Murillo R, Binda C, Lopez-Munoz F, Gobec S, Marco-Contelles J Acta Pharm Sin B. 2023 May;13(5):2152-2175. doi: 10.1016/j.apsb.2023.01.013. Epub , 2023 Jan 19. PMID:37250172<ref>PMID:37250172</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7zw3" 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: Gottinger A]] | |||
Latest revision as of 14:51, 23 October 2024
Crystal Structure of human MAO B in complex with (Z)-N-benzyl-1-(8-hydroxyquinolin-2-yl)methanimine oxide (inhibitor 19)Crystal Structure of human MAO B in complex with (Z)-N-benzyl-1-(8-hydroxyquinolin-2-yl)methanimine oxide (inhibitor 19)
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. Publication Abstract from PubMedWe describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC(50) = 1.06 +/- 0.31 nmol/L) and hMAO-B (IC(50) = 4.46 +/- 0.18 mumol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1deltaE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19. 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.,Knez D, Diez-Iriepa D, Chioua M, Gottinger A, Denic M, Chantegreil F, Nachon F, Brazzolotto X, Skrzypczak-Wiercioch A, Meden A, Pislar A, Kos J, Zakelj S, Stojan J, Salat K, Serrano J, Fernandez AP, Sanchez-Garcia A, Martinez-Murillo R, Binda C, Lopez-Munoz F, Gobec S, Marco-Contelles J Acta Pharm Sin B. 2023 May;13(5):2152-2175. doi: 10.1016/j.apsb.2023.01.013. Epub , 2023 Jan 19. PMID:37250172[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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