1gpn
From Proteopedia
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[[Image:1gpn.gif|left|200px]] | [[Image:1gpn.gif|left|200px]] | ||
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'''STRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH HUPERZINE B AT 2.35A RESOLUTION''' | '''STRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH HUPERZINE B AT 2.35A RESOLUTION''' | ||
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[[Category: Silman, I.]] | [[Category: Silman, I.]] | ||
[[Category: Sussman, J L.]] | [[Category: Sussman, J L.]] | ||
| - | [[Category: | + | [[Category: Alzheimer's disease]] |
| - | [[Category: | + | [[Category: Cholinesterase]] |
| - | [[Category: | + | [[Category: Huperzine some]] |
| - | [[Category: | + | [[Category: Huperzine b]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 17:51:46 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 14:51, 2 May 2008
STRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH HUPERZINE B AT 2.35A RESOLUTION
Overview
Kinetic and structural data are presented on the interaction with Torpedo californica acetylcholinesterase (TcAChE) of (+)-huperzine A, a synthetic enantiomer of the anti-Alzheimer drug, (-)-huperzine A, and of its natural homologue (-)-huperzine B. (+)-Huperzine A and (-)-huperzine B bind to the enzyme with dissociation constants of 4.30 and 0.33 microM, respectively, compared to 0.18 microM for (-)-huperzine A. The X-ray structures of the complexes of (+)-huperzine A and (-)-huperzine B with TcAChE were determined to 2.1 and 2.35 A resolution, respectively, and compared to the previously determined structure of the (-)-huperzine A complex. All three interact with the "anionic" subsite of the active site, primarily through pi-pi stacking and through van der Waals or C-H.pi interactions with Trp84 and Phe330. Since their alpha-pyridone moieties are responsible for their key interactions with the active site via hydrogen bonding, and possibly via C-H.pi interactions, all three maintain similar positions and orientations with respect to it. The carbonyl oxygens of all three appear to repel the carbonyl oxygen of Gly117, thus causing the peptide bond between Gly117 and Gly118 to undergo a peptide flip. As a consequence, the position of the main chain nitrogen of Gly118 in the "oxyanion" hole in the native enzyme becomes occupied by the carbonyl of Gly117. Furthermore, the flipped conformation is stabilized by hydrogen bonding of Gly117O to Gly119N and Ala201N, the other two functional elements of the three-pronged "oxyanion hole" characteristic of cholinesterases. All three inhibitors thus would be expected to abolish hydrolysis of all ester substrates, whether charged or neutral.
About this Structure
1GPN is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.
Reference
X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement., Dvir H, Jiang HL, Wong DM, Harel M, Chetrit M, He XC, Jin GY, Yu GL, Tang XC, Silman I, Bai DL, Sussman JL, Biochemistry. 2002 Sep 3;41(35):10810-8. PMID:12196020 Page seeded by OCA on Fri May 2 17:51:46 2008
