Factor VIIa: Difference between revisions

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====Stereochemistry of the tetrahedral intermediate====

Upon attack on an amide bond, the lone electron pairs of the oxyanion and the nitrogen of the leaving group have to be antiperiplanar to the new bond. Therefore the lone pair of the amine leaving group points away from His193-H+. For the chemistry to occur the nitrogen must undergo inversion to position the lone pair for protonation by His193-H+<ref>PMID:2514538</ref>.

[[Image:stereochemistry of N.jpg|center]]

====Substrate binding induces the formation of the oxyanion hole====

~~Unlike other serine proteases,~~ the ~~amide nitrogen~~ of ~~Gly342(193) in FVIIa~~ points away from the oxyanion hole ~~and the carbonyl oxygen of Lys341(192)~~ makes a H-bond with the gamma ~~oxygen~~ of ~~Ser344(195)when crystalized with small inhibitor molecules. However, upon crystallization with~~ a ~~peptidyl substrate D~~-~~Phe-Pro-Arg-chloromethylketone a flipping~~ of ~~the Lys341~~-~~Gly342(192-193)~~ peptide bond is ~~observed~~. This suggest that it is the substrate binding and not the TF cofactor binding that induces the oxyanion hole formation and functional active site geometry<ref>PMID: 16757484 </ref>.

Atypical conformation of the Lys192-Gly193 peptide bond has been observed. The carbonyl O of Lys192 which normally points away from the oxyanion hole makes a H-bond with the gamma O of Ser195 while the side chain of Glu143 fomrs a H-bond with the amide of Gly193. This Lys192-Gly193 peptide bond conformation in FVIIa is unconventional. This bond flips to the proper orientation only upon substrate binding. This suggest that it is the substrate binding and not the TF cofactor binding that induces the oxyanion hole formation and functional active site geometry<ref>PMID: 16757484 </ref>.

[[Image:oxyanion hole.jpg|center]]

Factor VIIa: Difference between revisions

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@@ Line 45: / Line 45: @@
 ====Stereochemistry of the tetrahedral intermediate====
-Upon attack on an amide bond, the lone electron pairs of the oxyanion and the nitrogen of the leaving group have to be antiperiplanar to the new bond. Therefore the lone pair of the amine leaving group points away from His193-H+. For the chemistry to occur the nitrogen must undergo inversion to position the lone pair for protonation by His193-H+<ref>PMID:2514538</ref>.
+ Upon attack on an amide bond, the lone electron pairs of the oxyanion and the nitrogen of the leaving group have to be antiperiplanar to the new bond. Therefore the lone pair of the amine leaving group points away from His193-H+. For the chemistry to occur the nitrogen must undergo inversion to position the lone pair for protonation by His193-H+<ref>PMID:2514538</ref>.
 [[Image:stereochemistry of N.jpg|center]]
 ====Substrate binding induces the formation of the oxyanion hole====
-Unlike other serine proteases, the amide nitrogen of Gly342(193) in FVIIa points away from the oxyanion hole and the carbonyl oxygen of Lys341(192) makes a H-bond with the gamma oxygen of Ser344(195)when crystalized with small inhibitor molecules. However, upon crystallization with a peptidyl substrate D-Phe-Pro-Arg-chloromethylketone a flipping of the Lys341-Gly342(192-193) peptide bond is observed. This suggest that it is the substrate binding and not the TF cofactor binding that induces the oxyanion hole formation and functional active site geometry<ref>PMID: 16757484 </ref>.
+Atypical conformation of the Lys192-Gly193 peptide bond has been observed. The carbonyl O of Lys192 which normally points away from the oxyanion hole makes a H-bond with the gamma O of Ser195 while the side chain of Glu143 fomrs a H-bond with the amide of Gly193. This Lys192-Gly193 peptide bond conformation in FVIIa is unconventional. This bond flips to the proper orientation only upon substrate binding. This suggest that it is the substrate binding and not the TF cofactor binding that induces the oxyanion hole formation and functional active site geometry<ref>PMID: 16757484 </ref>.
 [[Image:oxyanion hole.jpg|center]]