3F8G

The X-ray structure of a dimeric variant of human pancreatic ribonuclease with high cytotoxic and antitumor activities

3F8G の概要

• エントリーDOI: 10.2210/pdb3f8g/pdb
• 関連するPDBエントリー: 1BSR 1E21 1R3M 2K11
• 分子名称: Ribonuclease pancreatic, SULFATE ION (3 entities in total)
• 機能のキーワード: antitumor agent, ribonuclease, 3d domain swapping, unswapped dimer, dimers, endonuclease, glycoprotein, hydrolase, nuclease, secreted
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P07998
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28708.46

構造登録者

Merlino, A.,Avella, G.,Mazzarella, L.,Sica, F. (登録日: 2008-11-12, 公開日: 2009-02-10, 最終更新日: 2024-11-27)

主引用文献

Merlino, A.,Avella, G.,Di Gaetano, S.,Arciello, A.,Piccoli, R.,Mazzarella, L.,Sica, F.
Structural features for the mechanism of antitumor action of a dimeric human pancreatic ribonuclease variant.
Protein Sci., 18:50-57, 2009

PubMed Abstract: A specialized class of RNases shows a high cytotoxicity toward tumor cell lines, which is critically dependent on their ability to reach the cytosol and to evade the action of the ribonuclease inhibitor (RI). The cytotoxicity and antitumor activity of bovine seminal ribonuclease (BSRNase), which exists in the native state as an equilibrium mixture of a swapped and an unswapped dimer, are peculiar properties of the swapped form. A dimeric variant (HHP2-RNase) of human pancreatic RNase, in which the enzyme has been engineered to reproduce the sequence of BSRNase helix-II (Gln28-->Leu, Arg31-->Cys, Arg32-->Cys, and Asn34-->Lys) and to eliminate a negative charge on the surface (Glu111-->Gly), is also extremely cytotoxic. Surprisingly, this activity is associated also to the unswapped form of the protein. The crystal structure reveals that on this molecule the hinge regions, which are highly disordered in the unswapped form of BSRNase, adopt a very well-defined conformation in both subunits. The results suggest that the two hinge peptides and the two Leu28 side chains may provide an anchorage to a transient noncovalent dimer, which maintains Cys31 and Cys32 of the two subunits in proximity, thus stabilizing a quaternary structure, similar to that found for the noncovalent swapped dimer of BSRNase, that allows the molecule to escape RI and/or to enhance the formation of the interchain disulfides.

PubMed: 19177350
DOI: 10.1002/pro.6

実験手法

X-RAY DIFFRACTION (2.6 Å)