7zpb

From Proteopedia

(Difference between revisions)

Current revision

Structure of hemiacetylated human butyrylcholinesterase upon reaction with 8-(3-(4-(prop-2-yn-1-yl)piperazin-1-yl)propoxy)quinoline-2-carbaldehyde

Structural highlights

7zpb is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.31Å
Ligands:	, , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CHLE_HUMAN Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:177400. BChE deficiency is a metabolic disorder characterized by prolonged apnoea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency. BChE deficiency is a multifactorial disorder. The hereditary condition is transmitted as an autosomal recessive trait.

Function

CHLE_HUMAN Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.^[1] ^[2]

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^[3]

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

References

↑ Chilukuri N, Duysen EG, Parikh K, diTargiani R, Doctor BP, Lockridge O, Saxena A. Adenovirus-transduced human butyrylcholinesterase in mouse blood functions as a bioscavenger of chemical warfare nerve agents. Mol Pharmacol. 2009 Sep;76(3):612-7. doi: 10.1124/mol.109.055665. Epub 2009 Jun, 19. PMID:19542320 doi:10.1124/mol.109.055665
↑ Amitay M, Shurki A. The structure of G117H mutant of butyrylcholinesterase: nerve agents scavenger. Proteins. 2009 Nov 1;77(2):370-7. doi: 10.1002/prot.22442. PMID:19452557 doi:10.1002/prot.22442
↑ Knez D, Diez-Iriepa D, Chioua M, Gottinger A, Denic M, Chantegreil F, Nachon F, Brazzolotto X, Skrzypczak-Wiercioch A, Meden A, Pišlar A, Kos J, Žakelj S, Stojan J, Sałat K, Serrano J, Fernández AP, Sánchez-García A, Martínez-Murillo R, Binda C, López-Muñoz F, Gobec S, Marco-Contelles J. 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases. Acta Pharm Sin B. 2023 May;13(5):2152-2175. PMID:37250172 doi:10.1016/j.apsb.2023.01.013

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7zpb"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7zpb]] is a 1 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=7ZPB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZPB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JS0:[8-[3-(4-prop-2-ynylpiperazin-1-yl)propoxy]quinolin-2-yl]methanol'>JS0</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PPI:PROPANOIC+ACID'>PPI</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.31&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JS0:[8-[3-(4-prop-2-ynylpiperazin-1-yl)propoxy]quinolin-2-yl]methanol'>JS0</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PPI:PROPANOIC+ACID'>PPI</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7zpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zpb OCA], [https://pdbe.org/7zpb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zpb RCSB], [https://www.ebi.ac.uk/pdbsum/7zpb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zpb ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 == Function ==
 [https://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN] Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.<ref>PMID:19542320</ref> <ref>PMID:19452557</ref>
+<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.
+-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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7zpb" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

7zpb

From Proteopedia

Current revision

Structure of hemiacetylated human butyrylcholinesterase upon reaction with 8-(3-(4-(prop-2-yn-1-yl)piperazin-1-yl)propoxy)quinoline-2-carbaldehyde

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox