Herceptin - Mechanism of Action

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Crystal structure of extracellular domain of human HER2 complexed with Herceptin Fab (PDB entry 1n8z)

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(Figure 6) This picture illustrates the mechanism in which EGFR, HER3, and HER4 change conformation in order to dimerize and activate further cell signaling. A) Sub-domain I (green) is sepearated from sub-domain III (blue). Sub-domain II (red) forms an interaction (purple line) with sub-domain IV (yellow). This conformation allows sub-domain II to be hidden and unavailable for dimerization. B) The interaction between sub-domain II and sub-domain IV can be temporarily broken allowing for the receptor to become more available for ligand-binding. C) Upon ligand-binding, if the interaction of sub-domain II and IV is still formed, the interaction between sub-domain II and sub-domain IV is broken and allows sub-domain II to become available for homo- or hetero-dimerization with another receptor from the HER family.
(Figure 6) This picture illustrates the mechanism in which EGFR, HER3, and HER4 change conformation in order to dimerize and activate further cell signaling. A) Sub-domain I (green) is sepearated from sub-domain III (blue). Sub-domain II (red) forms an interaction (purple line) with sub-domain IV (yellow). This conformation allows sub-domain II to be hidden and unavailable for dimerization. B) The interaction between sub-domain II and sub-domain IV can be temporarily broken allowing for the receptor to become more available for ligand-binding. C) Upon ligand-binding, if the interaction of sub-domain II and IV is still formed, the interaction between sub-domain II and sub-domain IV is broken and allows sub-domain II to become available for homo- or hetero-dimerization with another receptor from the HER family[12].

References

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  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 "HER2 Dimerization: A Key Component of Oncogenic Signaling in HER2 Breast Cancer." HER2+ Breast Cancer. Genentech, n.d. Web. 09 Nov. 2012. <http://www.biooncology.com/research-education/hdis/her2-dimerization/index.html>.
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