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1gqs
From Proteopedia
| 1gqs, resolution 3.00Å () | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Sites: | , and | ||||||||
| Ligands: | , | ||||||||
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 | ||||||||
| Related: | 1acj, 1acl, 1amn, 1ax9, 1cfj, 1dx6, 1e3q, 1e66, 1ea5, 1eea, 1eve, 1fss, 1gpk, 1gpn, 1hbj, 1oce, 1qid, 1qie, 1qif, 1qig, 1qih, 1qii, 1qij, 1qik, 1qim, 1qti, 1som, 1vot, 1vxo, 1vxr, 2ace, 2ack, 2dfp, 3ace, 4ace, 1gqr | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Contents |
ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH NAP
(see also AChE inhibitors and substrates (Part III))
Rivastigmine, a carbamate inhibitor of acetylcholinesterase, is already in use for treatment of Alzheimer's disease under the trade name of Exelon. Rivastigmine carbamylates Torpedo californica acetylcholinesterase very slowly (k(i) = 2.0 M(-1) min(-1)), whereas the bimolecular rate constant for inhibition of human acetylcholinesterase is >1600-fold higher (k(i) = 3300 M(-1) min(-1)). For human butyrylcholinesterase and for Drosophila melanogaster acetylcholinesterase, carbamylation is even more rapid (k(i) = 9 x 10(4) and 5 x 10(5) M(-1) min(-1), respectively). Spontaneous reactivation of all four conjugates is very slow, with <10% reactivation being observed for the Torpedo enzyme after 48 h. The crystal structure of the conjugate of rivastigmine with Torpedo acetylcholinesterase was determined to 2.2 A resolution. It revealed that the carbamyl moiety is covalently linked to the active-site serine, with the leaving group, (-)-S-3-[1-(dimethylamino)ethyl]phenol, being retained in the "anionic" site. A significant movement of the active-site histidine (H440) away from its normal hydrogen-bonded partner, E327, was observed, resulting in disruption of the catalytic triad. This movement may provide an explanation for the unusually slow kinetics of reactivation.
Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine., Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I, Biochemistry. 2002 Mar 19;41(11):3555-64. PMID:11888271
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Rivastigmine (Exelon) is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. Here is the of the rivastigmine/TcAChE complex. The carbamyl moiety of rivastigmine is to the active-site S200 Oγ. The leaving group of rivastigmine, ((−)-S-3-[1-(dimethylamino)ethyl]phenol) (NAP) is also seen in the active-site gorge, but it is from the carbamyl moiety, hence, carbamylation took place. The of NAP/TcAChE NAP (colored magenta) (without the carbamyl moiety) was determined (present entry - 1gqs). The TcAChE active-site residues interacting with NAP are colored violet. NAP is located in relatively similar region of the TcAChE active site, but with different orientation to that of the NAP moiety of rivastigmine. Only H440 and F330 significantly change their side-chain conformations. of the TcAChE active sites in 4 different complexes (with rivastigmine (1gqr), NAP (1gqs), ACh (2ace), and the additional AChE inhibitor VX (1vxr)) revealed that the conformation of H440 in the NAP/TcAChE is similar to that of native TcAChE (2ace), but the distance between H440 Nδ and E327 Oε is significantly longer in the rivastigmine/TcAChE and the VX/TcAChE complexes. This structural change disrupts the catalytic triad consisting of E327, H440, and S200. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine.
About this Structure
1GQS is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.
Additional Resources
For additional information, see: Alzheimer's Disease
Reference
Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine., Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I, Biochemistry. 2002 Mar 19;41(11):3555-64. PMID:11888271
Page seeded by OCA on Tue Jul 1 05:55:07 2008
