RING finger E(3) ubiquitin ligases: structure and drug discovery.
The RING (Really Interesting New Gene) family is the largest type of E3 ubiquitin ligases. RING finger domains bind two zinc ions in a unique "cross-brace" arrangement through a defined motif of cysteine and histidine residues. This arrangement endows the RING domain with a globular conformation, characterized by a central alpha-helix and variable-length loops separated by several small beta-strands. RING E3 ubiquitin ligases, play an essential role in the regulation of many biologic processes and defects in some of them are involved in cancer development. Furthermore, some RING E3 ligases are frequently overexpressed in human cancers. Today, RING ligases represent potentially molecular targets for disease intervention and could act as prognostic biomarkers. Targeting specific RING E3 ligases could lead to the development of a novel class of anticancer drugs. However RING fingers exhibit remarkable variations in their sequence and their topology characteristics. Structure determination of new RING finger domain is in the core of the design of new pharmaceuticals and what is presented in this article is a thorough review of achievements on the NMR or Xray structure determinations. Protein preparation protocols along with analysis of the structural features of known RING finger are also presented.
Chasapis
Christos T
CT
Department of Pharmacy, University of Patras, Panepistimioupoli - Rion, GR-26504, Patras, Greece. cchasapis@upatras.gr
Spyroulias
Georgios A
GA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011487:Protein Conformation; D054829:RING Finger Domains / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D000970:Antineoplastic Agents; D044767:Ubiquitin-Protein Ligases