Beta secretase: Difference between revisions
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B. In the second pathway, β-secretase cleaves APP at the N-terminus of Aβ, creating a fragment of sAPPβ. Then γ-secretase cleaves APP at the C-terminus of Aβ, which exists along the transmembrane domain of APP. At this point, Aβ is released and allowed to accumulate with other fragments, forming plaques. | B. In the second pathway, β-secretase cleaves APP at the N-terminus of Aβ, creating a fragment of sAPPβ. Then γ-secretase cleaves APP at the C-terminus of Aβ, which exists along the transmembrane domain of APP. At this point, Aβ is released and allowed to accumulate with other fragments, forming plaques. | ||
β- | β-Secretase is able to cleave Aβ at its N-terminus due to the nucleophilic attack that occurs upon the the active site of β-secretase. After the water molecule is coordinated between the carbonyls of the aspartates and the N-terminus of Aβ, the two are able to react, forcing the N-terminus to break its bond with sAPPβ. | ||
==Inhibition of Beta Secretase== | ==Inhibition of Beta Secretase== | ||
<applet load="1w51" size="300" color="white" frame="true" align="left" caption="β-secretase complexed with OM99-2" scene="Beta_secretase/Om99-2/1" /> | |||
Due to β-secretase's function in the production of Aβ, it has become a very popular target for therapeutic drugs. An example of one such developed drug is OM99-2, which comes from Astex Technology. | |||
[[Image:OM99-2.PNG|thumb|right|Structure of OM99-2.]] | |||
Once the inhibitor moves into place, its positively charged amine group and its hydroxyl group start to interact with β-secretase's active site. The nucelophilic attack on the aspartate's carbonyls binds OM99-2 to β-secretase. As OM99-2 becomes situated within β-secretase's binding pocket, the flap closes upon OM99-2. The flap's residues Thr72 and Gln73 bind with one of OM99-2's carbonyl groups. The 10s loop remains open to allow OM99-2 to interact with the S3 pocket. At this point <scene name='Beta_secretase/Om99-2finished/1'>OM99-2 is locked securely within β-secretase's binding pocket</scene>. | |||
[[Image:Om99 reaction.PNG|center]] | |||
OM99-2 remains stabilized in the pocket by binding to the other pockets of β-secretase (S1, S2, S2', and S3). Additionally, OM99-2 is able to interact with other residues in β-secretase (in this case Gly34 and Thr232), though this is not the case for all inhibitors. | |||
==References== | ==References== | ||
