Acetylcholinesterase
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====Rivastigmine==== | ====Rivastigmine==== | ||
- | <scene name='1gqr/Com_view/1'>Rivastigmine</scene> ([[Exelon]]) is a carbamate inhibitor of AChE, and it is currenly used in therapy of [[Alzheimer's Disease]]. <span style="color:yellow;background-color:black;font-weight:bold;">Rivastigmine (colored yellow)</span> interacts with ''Tc''AChE <span style="color:lime;background-color:black;font-weight:bold;">(colored green)</span> at the <scene name='1gqr/Active_site/4'>active-site gorge</scene> ([[1gqr]]). The carbamyl moiety of rivastigmine is <scene name='1gqr/Active_site/9'>covalently bound</scene> to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is <scene name='1gqr/Active_site/6'>separated</scene> from the carbamyl moiety, hence, carbamylation took place. The <scene name='1gqr/Active_site/7'>crystal structure</scene> of ''Tc''AChE/<font color='magenta'><b>NAP (colored magenta)</b></font> is known ([[1gqs]]). The <font color='violet'><b>''Tc''AChE active-site residues</b></font> which are interacting with NAP are <font color='violet'><b>colored violet</b></font>. NAP is located in a similar region of ''Tc''AChE active site, but with different orientation than that of the <span style="color:yellow;background-color:black;font-weight:bold;">NAP part (colored yellow)</span> in the ''Tc''AChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. <scene name='1gqr/Active_site/8'>Overlap</scene> of the ''Tc''AChE active sites in 4 different structures <span style="color:lime;background-color:black;font-weight:bold;">''Tc''AChE</span>/rivastigmine ([[1gqr]]), <font color='violet'><b>''Tc''AChE</b></font>/<font color='magenta'><b>NAP</b></font> ([[1gqs]]), <span style="color:cyan;background-color:black;font-weight:bold;">native ''Tc''AChE</span> ([[2ace]]), and ''Tc''AChE/'''VX''' ([[1vxr]], ''Tc''AChE colored white and VX black) reveals that the conformation of H440 in the ''Tc''AChE/NAP structure is very similar its conformation in the native ''Tc''AChE ([[2ace]]), but the distance between H440 Nδ and E327 Oε is significantly longer in the ''Tc''AChE/rivastigmine and the ''Tc''AChE/'''VX''' complexes. This structural change disrupts the [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by | + | <scene name='1gqr/Com_view/1'>Rivastigmine</scene> ([[Exelon]]) is a carbamate inhibitor of AChE, and it is currenly used in therapy of [[Alzheimer's Disease]]. <span style="color:yellow;background-color:black;font-weight:bold;">Rivastigmine (colored yellow)</span> interacts with ''Tc''AChE <span style="color:lime;background-color:black;font-weight:bold;">(colored green)</span> at the <scene name='1gqr/Active_site/4'>active-site gorge</scene> ([[1gqr]]). The carbamyl moiety of rivastigmine is <scene name='1gqr/Active_site/9'>covalently bound</scene> to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is <scene name='1gqr/Active_site/6'>separated</scene> from the carbamyl moiety, hence, carbamylation took place. The <scene name='1gqr/Active_site/7'>crystal structure</scene> of ''Tc''AChE/<font color='magenta'><b>NAP (colored magenta)</b></font> is known ([[1gqs]]). The <font color='violet'><b>''Tc''AChE active-site residues</b></font> which are interacting with NAP are <font color='violet'><b>colored violet</b></font>. NAP is located in a similar region of ''Tc''AChE active site, but with different orientation than that of the <span style="color:yellow;background-color:black;font-weight:bold;">NAP part (colored yellow)</span> in the ''Tc''AChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. <scene name='1gqr/Active_site/8'>Overlap</scene> of the ''Tc''AChE active sites in 4 different structures <span style="color:lime;background-color:black;font-weight:bold;">''Tc''AChE</span>/rivastigmine ([[1gqr]]), <font color='violet'><b>''Tc''AChE</b></font>/<font color='magenta'><b>NAP</b></font> ([[1gqs]]), <span style="color:cyan;background-color:black;font-weight:bold;">native ''Tc''AChE</span> ([[2ace]]), and ''Tc''AChE/'''VX''' ([[1vxr]], ''Tc''AChE colored white and VX black) reveals that the conformation of H440 in the ''Tc''AChE/NAP structure is very similar its conformation in the native ''Tc''AChE ([[2ace]]), but the distance between H440 Nδ and E327 Oε is significantly longer in the ''Tc''AChE/rivastigmine and the ''Tc''AChE/'''VX''' complexes. This structural change disrupts the [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by [[Rivastigmine]] <ref name="Bar-On">PMID:11888271</ref>. |
=== The second generation of AD drugs - bivalent AChE inhibitors === | === The second generation of AD drugs - bivalent AChE inhibitors === |
Revision as of 12:01, 18 February 2016
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Contents |
3D Structures of AChE
See 3D structures of acetylcholinesterase
Additional Resources
For additional information, see:
Alzheimer's Disease
AChE inhibitors and substrates
External Links
- Acetylcholinesterase Tutorial by Karl Oberholser, Messiah College
- PDB Molecule of the Month - Acetylcholinesterase
- Movies: X-ray Damage in ACh & Nature's Vacuum Cleaner by R. Gillilan, Cornell Univ
References
- ↑ Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science. 1991 Aug 23;253(5022):872-9. PMID:1678899
- ↑ Botti SA, Felder CE, Lifson S, Sussman JL, Silman I. A modular treatment of molecular traffic through the active site of cholinesterase. Biophys J. 1999 Nov;77(5):2430-50. PMID:10545346
- ↑ 3.0 3.1 Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL. Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A. Nat Struct Biol. 1997 Jan;4(1):57-63. PMID:8989325
- ↑ Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEBS Lett. 1999 Dec 17;463(3):321-6. PMID:10606746
- ↑ Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9031-5. PMID:8415649
- ↑ Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I. Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry. 2002 Mar 19;41(11):3555-64. PMID:11888271
- ↑ Haviv H, Wong DM, Greenblatt HM, Carlier PR, Pang YP, Silman I, Sussman JL. Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase. J Am Chem Soc. 2005 Aug 10;127(31):11029-36. PMID:16076210 doi:http://dx.doi.org/10.1021/ja051765f
- ↑ 8.0 8.1 Ravelli RB, Raves ML, Ren Z, Bourgeois D, Roth M, Kroon J, Silman I, Sussman JL. Static Laue diffraction studies on acetylcholinesterase. Acta Crystallogr D Biol Crystallogr. 1998 Nov 1;54(Pt 6 Pt 2):1359-66. PMID:10089512
- ↑ 9.0 9.1 Harel M, Sonoda LK, Silman I, Sussman JL, Rosenberry TL. Crystal structure of thioflavin T bound to the peripheral site of Torpedo californica acetylcholinesterase reveals how thioflavin T acts as a sensitive fluorescent reporter of ligand binding to the acylation site. J Am Chem Soc. 2008 Jun 25;130(25):7856-61. Epub 2008 May 31. PMID:18512913 doi:http://dx.doi.org/10.1021/ja7109822
- ↑ Greenblatt HM, Guillou C, Guenard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL. The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design. J Am Chem Soc. 2004 Dec 1;126(47):15405-11. PMID:15563167 doi:http://dx.doi.org/10.1021/ja0466154
- ↑ Kryger G, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure. 1999 Mar 15;7(3):297-307. PMID:10368299
- ↑ Sanson B, Nachon F, Colletier JP, Froment MT, Toker L, Greenblatt HM, Sussman JL, Ashani Y, Masson P, Silman I, Weik M. Crystallographic Snapshots of Nonaged and Aged Conjugates of Soman with Acetylcholinesterase, and of a Ternary Complex of the Aged Conjugate with Pralidoxime (dagger). J Med Chem. 2009 Jul 30. PMID:19642642 doi:10.1021/jm900433t
- ↑ Paz A, Roth E, Ashani Y, Xu Y, Shnyrov VL, Sussman JL, Silman I, Weiner L. Structural and functional characterization of the interaction of the photosensitizing probe methylene blue with Torpedo californica acetylcholinesterase. Protein Sci. 2012 Jun 1. doi: 10.1002/pro.2101. PMID:22674800 doi:10.1002/pro.2101
Treatments:AChE Inhibitor References
Treatments:Alzheimer's Disease
Proteopedia Page Contributors and Editors (what is this?)
Michal Harel, Joel L. Sussman, Alexander Berchansky, David Canner, Eran Hodis, Clifford Felder, Jaime Prilusky, Harry Greenblatt, Yechun Xu