National Natural Science Foundation of China (NSFC)
82073750
China
Citation
Journal: Proc Natl Acad Sci U S A / Year: 2025 Title: Computational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody-drug conjugates. Authors: Xuefei Bai / Lingyi Xu / Zhe Wang / Xinlei Zhuang / Jiangtao Ning / Yanping Sun / Haibin Wang / Yugang Guo / Yingchun Xu / Jiangtao Guo / Shuqing Chen / Liqiang Pan / Abstract: Recurrent missense mutations in the human epidermal growth factor receptor 2 (HER2) have been identified across various human cancers. Among these mutations, the active S310F mutation in the HER2 ...Recurrent missense mutations in the human epidermal growth factor receptor 2 (HER2) have been identified across various human cancers. Among these mutations, the active S310F mutation in the HER2 extracellular domain stands out as not only oncogenic but also confers resistance to pertuzumab, an antibody drug widely used in clinical cancer therapy, by impeding its binding. In this study, we have successfully employed computational-aided rational design to undertake directed evolution of pertuzumab, resulting in the creation of an evolved pertuzumab variant named Ptz-SA. This variant, with only two mutations (T30S/D31A) located on its heavy chain, effectively reinstates binding to the mutated antigen, at the expense of a 35-fold reduction in binding affinity to HER2 (S310F) compared to the wild-type pair. Subsequently, Ptz-SA demonstrates potent killing capacity through antigen-dependent cytotoxicity. Moreover, upon engineering Ptz-SA into antibody-drug conjugates, such as Ptz-SA-MMAE, it manifests notable in vitro and in vivo antitumor efficacy by efficiently delivering cytotoxic payload into tumor cells expressing HER2 (S310F). Cryoelectron microscopy studies elucidate the molecular mechanism underlying the restored binding ability of Ptz-SA toward the S310F mutation. The steric hindrance induced by the S310F mutation is efficiently circumvented by the T30S and D31A mutations, which provides adequate space to accommodate the larger phenylalanine. Additionally, Ptz-SA also exhibits binding capacity to HER2 (S310Y), another mutation occurring at the S310 site of HER2 with high frequency. The computational-aided evolution of pertuzumab provides an alternative strategy for overcoming point mutation-mediated resistance to therapeutic antibodies.
In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)
EMDB accession codes are about to change! (news from PDBe EMDB page)
The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
The EM Navigator/Yorodumi systems omit the EMD- prefix.
Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator
Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.
Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi
Movie
Controller
Open data
Basic information
Map data
Sample
Keywords
Function and homology information
Homo sapiens (human)
Authors
China, 1 items 
Citation
Structure visualization
Downloads & links
emd_62753.png
http://ftp.pdbj.org/pub/emdb/structures/EMD-62753
Z (Sec.)
Y (Row.)
X (Col.)
Sample components
Processing
Electron microscopy
FIELD EMISSION GUN
