7bo3

From Proteopedia

(Difference between revisions)

Revision as of 12:31, 1 February 2024

Human Butyrylcholinesterase in complex with N-(2-(1H-Indol-3-yl)ethyl)-2-cycloheptyl-N-methylethan-1-amine

Structural highlights

7bo3 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 2.2Å
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

Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp(3)-rich analogues with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold). Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme). Additionally, N-hydroxyindole was discovered as a novel leaving group chemotype. The covalent mechanism of action was confirmed by time-dependency experiments, progress curve analysis, and indirectly by co-crystallization with the human recombinant enzyme. Two crystal structures of BChE-inhibitor complexes were solved and coupled with the supporting molecular dynamics simulations increased our understanding of the structure-activity relationship, while also providing the necessary structural information for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors.

From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series.,Meden A, Knez D, Brazzolotto X, Nachon F, Dias J, Svete J, Stojan J, Groselj U, Gobec S Eur J Med Chem. 2022 Mar 7;234:114248. doi: 10.1016/j.ejmech.2022.114248. PMID:35299116^[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
↑ Meden A, Knez D, Brazzolotto X, Nachon F, Dias J, Svete J, Stojan J, Groselj U, Gobec S. From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series. Eur J Med Chem. 2022 Mar 7;234:114248. doi: 10.1016/j.ejmech.2022.114248. PMID:35299116 doi:http://dx.doi.org/10.1016/j.ejmech.2022.114248

1 Structural highlights
2 Disease
3 Function
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/7bo3"

@@ Line 3: / Line 3: @@
 <StructureSection load='7bo3' size='340' side='right'caption='[[7bo3]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7bo3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BO3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BO3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7bo3]] 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=7BO3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BO3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IA4:~{N}-(2-cycloheptylethyl)-2-(1~{H}-indol-3-yl)-~{N}-methyl-ethanamine'>IA4</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=SIA:O-SIALIC+ACID'>SIA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</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]] 2.2&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Cholinesterase Cholinesterase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.8 3.1.1.8] </span></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=IA4:~{N}-(2-cycloheptylethyl)-2-(1~{H}-indol-3-yl)-~{N}-methyl-ethanamine'>IA4</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=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=7bo3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bo3 OCA], [https://pdbe.org/7bo3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bo3 RCSB], [https://www.ebi.ac.uk/pdbsum/7bo3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bo3 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN]] Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:[https://omim.org/entry/177400 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.
+[https://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN] Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:[https://omim.org/entry/177400 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 ==
-[[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>
+[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 ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 7bo3" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Butyrylcholinesterase 3D structures|Butyrylcholinesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Cholinesterase]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Brazzolotto, X]]
+[[Category: Brazzolotto X]]
-[[Category: Gobec, S]]
+[[Category: Gobec S]]
-[[Category: Knez, D]]
+[[Category: Knez D]]
-[[Category: Meden, A]]
+[[Category: Meden A]]
-[[Category: Nachon, F]]
+[[Category: Nachon F]]
-[[Category: Butyrylcholinesterase]]
-[[Category: Complex]]
-[[Category: Hydrolase]]
-[[Category: Inhibitor]]

7bo3

From Proteopedia

Revision as of 12:31, 1 February 2024

Human Butyrylcholinesterase in complex with N-(2-(1H-Indol-3-yl)ethyl)-2-cycloheptyl-N-methylethan-1-amine

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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