6RTI

X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with aptamer A9g

6RTI の概要

• エントリーDOI: 10.2210/pdb6rti/pdb
• 分子名称: Glutamate carboxypeptidase 2, (4S)-2-METHYL-2,4-PENTANEDIOL, ACETATE ION, ... (12 entities in total)
• 機能のキーワード: glutamate carboxypeptidase ii (gcpii); naaladase; prostate-specific membrane antigen; aptamer, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 98360.82

構造登録者

Motlova, L.,Kolenko, P.,Barinka, C. (登録日: 2019-05-24, 公開日: 2020-06-10, 最終更新日: 2024-11-13)

主引用文献

Ptacek, J.,Zhang, D.,Qiu, L.,Kruspe, S.,Motlova, L.,Kolenko, P.,Novakova, Z.,Shubham, S.,Havlinova, B.,Baranova, P.,Chen, S.J.,Zou, X.,Giangrande, P.,Barinka, C.
Structural basis of prostate-specific membrane antigen recognition by the A9g RNA aptamer.
Nucleic Acids Res., 48:11130-11145, 2020

PubMed Abstract: Prostate-specific membrane antigen (PSMA) is a well-characterized tumor marker associated with prostate cancer and neovasculature of most solid tumors. PSMA-specific ligands are thus being developed to deliver imaging or therapeutic agents to cancer cells. Here, we report on a crystal structure of human PSMA in complex with A9g, a 43-bp PSMA-specific RNA aptamer, that was determined to the 2.2 Å resolution limit. The analysis of the PSMA/aptamer interface allows for identification of key interactions critical for nanomolar binding affinity and high selectivity of A9g for human PSMA. Combined with in silico modeling, site-directed mutagenesis, inhibition experiments and cell-based assays, the structure also provides an insight into structural changes of the aptamer and PSMA upon complex formation, mechanistic explanation for inhibition of the PSMA enzymatic activity by A9g as well as its ligand-selective competition with small molecules targeting the internal pocket of the enzyme. Additionally, comparison with published protein-RNA aptamer structures pointed toward more general features governing protein-aptamer interactions. Finally, our findings can be exploited for the structure-assisted design of future A9g-based derivatives with improved binding and stability characteristics.

PubMed: 32525981
DOI: 10.1093/nar/gkaa494

実験手法

X-RAY DIFFRACTION (2.2 Å)