Journal:Acta Cryst D:S2059798319006995
From Proteopedia
Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cellsZhenyi Wang, Liansheng Cheng, Gongrui Guo, Baoyun Cheng, Siyi Hu, Hongmin Zhang, Zhongliang Zhu and Liwen Niu [1] Molecular Tour (PDB entry 6j71). In ECD, the subdomains I, II, III and IV are colored red, green, blue and yellow, respectively. The light chain (VL) and heavy chain (VH) of HuA21 scFv are colored magenta and cyan, respectively. , respectively. . The Interface of the HuA21-HER2 Complex are labelled L1, L2, L3, H1, H2 and H3 and colored paleyellow, limegreen, lightorange, palegreen, palecyan and lightpink, respectively. The other parts of HuA21 scFv are colored light gray. are labelled Loop I, Loop II and Loop III and colored lemon, orange and cyan. . The important residues on HER2 are shown as sticks and labelled with white characters. The key residues on HuA21 are colored the same as in the previous scene and labelled with red characters. Compared to chA21, HuA21 shows higher affinity towards HER2 ECD. While most interactions keep the same between chA21 and HuA21, structural superposition reveals that two important regions should contribute to the affinity improvement. One is the which forms hydrophobic interaction with residues P194 and P197 in loop III as well as hydrogen bond with the main chain carbonyl oxygen of residue C195 (Loop III). The newly formed hydrogen bond between Ne of W41 (L1) and the carbonyl oxygen of residue C195 (Loop III) pulls residue W41 (L1) near loop III and helps W41 (L1) forms extra hydrophobic interaction with residue P194 and P197 (Loop III). The important residues on HER2-chA21 are shown as sticks and labelled with white characters. The key residues on HER2-HuA21 are shown as sticks and labelled with red characters. The . As mentioned above, the side chain of residue Q170 (H1) forms bidentate hydrogen bonds with the main chain carbonyl oxygen of residue T186 (Loop III) and side chain carbonyl oxygen of residue N187 (Loop III). These extra hydrophobic interaction and hydrogen bonds should greatly enhance the interaction between HuA21 and HER2. . HuA21, Trastuzumab and Pertuzumab are labelled and colored slate, magenta and cyan, respectively. The HER2 subdomains I, II, III and IV are colored red, green, blue and yellow, respectively. PDB reference: HuA21-scFv in complex with the extracellular domain (ECD) of HER2 6j71. References
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