9HLW

Prostate Specific Membrane Antigen (PSMA) in complex with nanobody7

9HLW の概要

• エントリーDOI: 10.2210/pdb9hlw/pdb
• EMDBエントリー: 52273
• 分子名称: Glutamate carboxypeptidase 2, Nano body 7, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: nanobodies their prostate specific membrane antigen psma prostate cancer, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 206976.52

構造登録者

Alon, G.,Papo, N.,Zarivach, R.,Zalk, R. (登録日: 2024-12-05, 公開日: 2025-07-16, 最終更新日: 2025-07-23)

主引用文献

Alon-Zchut, G.,Zalk, R.,Huynh, T.T.,Zalutsky, M.R.,Weizmann, Y.,Zarivach, R.,Papo, N.
Structural analysis of nanobody interactions with their prostate-specific membrane antigen binding epitopes.
Int.J.Biol.Macromol., 320:145693-145693, 2025

PubMed Abstract: Prostate-specific membrane antigen (PSMA), overexpressed in prostate cancer, is a promising target for diagnostics and therapy. However, the monoclonal antibodies in current use for PSMA targeting and inhibition have suboptimal activities due to their poor tissue and cell penetration and slow normal tissue clearance. Potentially superior alternatives are nanobodies (NBs), the single-chain variable domains of heavy-chain antibodies derived from camelids. The advantages of NBs include small size (~15 kDa), ability to bind hidden epitopes, and rapid clearance. In contrast to most known PSMA inhibitors, which bind to the same catalytic site in PMSA, NBs can bind to different PSMA epitopes, facilitating heterovalent binding strategies that could enhance their therapeutic and diagnostic potential. The objective of this study was to map these binding epitopes and hence to acquire an atomic-resolution understanding of NB-PMSA binding by investigating the structural interactions between PSMA and three NBs (NB7, NB8, and NB37). Using cryo-electron microscopy to generate high-resolution structures of NB-PSMA complexes, we found that NB7 had the highest affinity for PSMA due to a larger interface and to stabilizing interactions, including salt bridges and π-π stacking. Notably, we also found that NB7 and NB8 can bind simultaneously to different PSMA epitopes without interfering with the function of PSMA (which is still not completely known), opening the way for the development of theranostic applications for prostate cancer treatment and imaging. Importantly, NB7 binds specifically to human PSMA but not to murine PSMA, due to key amino acid differences responsible for its species specificity.

PubMed: 40609945
DOI: 10.1016/j.ijbiomac.2025.145693

実験手法

ELECTRON MICROSCOPY (2.66 Å)