Crystal structure of human angiogenin with an engineered loop exhibits conformational flexibility at the functional regions of the molecule.

Human angiogenin (ANG) is an angiogenic molecule and a ribonucleolytic enzyme with significant amino acid sequence identity to pancreatic RNase A, plays a critical role in the establishment and growth of tumours. An association between ANG and cancer has been observed in more than 25 clinical studies to date. In addition, ANG has now been shown to be implicated in Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD). Structural and biochemical studies so far have showed several distinguishing features of ANG molecule compared to RNase A and provided details of the putative cell binding site, active site, nuclear translocation sequence and the roles of residues in binding and cleaving RNA. A key finding elucidated from the structural study on ANG is the presence of a 'blocked' C-terminus (part of the active site apparatus) compared with RNase A. Here we report the crystal structure of ANG with an 'engineered-loop' from eosinophil derived neurotoxin (a homologue of ANG) which has resulted with local perturbations (conformational flexibility) at the cell binding site and at the C-terminus of the molecule. This experimental observation will now provide a new avenue to design compounds (potent inhibitors) through a structure guided drug design route.