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RtcB is an essential human tRNA ligase required for ligating the 2',3'-cyclic phosphate and 5'-hydroxyl termini of cleaved tRNA halves during tRNA splicing and XBP1 fragments during endoplasmic reticulum stress. Activation of XBP1 has been implicated in various human tumors including breast cancer. Here we present, for the first time, a homology model of human RtcB (hRtcB) in complex with manganese and covalently bound GMP built from the Pyrococcus horikoshii RtcB (bRtcB) crystal structure, PDB ID 4DWQA. The structure is analyzed in terms of stereochemical quality, folding reliability, secondary structure similarity with bRtcB, druggability of the active site binding pocket and its metal-binding microenvironment. In comparison with bRtcB, loss of a manganese-coordinating water and movement of Asn226 (Asn202 in 4DWQA) to form metal-ligand coordination, demonstrates the uniqueness of the hRtcB model. Rotation of GMP leads to the formation of an additional metal-ligand coordination (Mn-O). Umbrella sampling simulations of Mn binding in wild type and the catalytically inactive C122A mutant reveal a clear reduction of Mn binding ability in the mutant, thus explaining the loss of activity therein. Our results furthermore clearly show that the GTP binding site of the enzyme is a well-defined pocket that can be utilized as target site for in silico drug discovery.

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10069 Background: Childhood cancers, a leading cause of childhood deaths, affect more than 200,000 children worldwide, of which >80% are from developing nations. This demands for proper measurement of the incidence of various childhood cancers which led to a novel study in assessing the burden of childhood cancers in eastern India through analysis of hospital-based cancer registry data from our institute in between January 2001- December 2011. Methods: 3,200pediatriccancer patients between 0-15 yearsdiagnosed by means of histological and cytological examinations were included in this study. Based on histopathological classification, cancer cases were distributed into 3 different age groups. Their respective family functioning, mental health, self-esteem and social competence were examined. Details of disease, tobacco usage along with socio demographic data were collected through standard questionnaires. Comparative measures of disease incidence were also calculated. For measuring the tolerance, different drugs were administered to patients. Results: The incidence of different malignancies was recorded which were Leukemia (34.9%), Lymphoma (24.1%), Hodgkin’s disease (18.1%), NHL (6.0%), Ewing’s sarcoma (4.9%), Rhabdomyosarcoma (3.6%), Neuroblastoma (2.0%), Brain tumour (9.9%), Wilm’s tumour (6.0%), Lymphoid Leukemia (26.9%), Myeloid Leukemia (7.9%), Germ cell tumour (4.2%), Osteosarcoma (4.0%), Retinoblastoma (2.0%) and Soft tissue sarcoma (2.3%). The disease free survival (DFS) for ALL was 76%, NHL (84%), Soft tissue sarcoma (78%), CML (98%), AML (48%) and germ cell tumour (95%). Finally, 53.33% patients were subjected to post-therapy assessment, of which 98% showed no after effect of therapy on growth chart, heart and endocrine function. The toxicity of grade III and IV chemotherapy ranges from 10-20%. Conclusions: Based on our study, the most happening cancer was Leukemia (34.9%) followed by Lymphoma (24.1%) and soft tissue sarcoma (18%). The overall disease free survival for pediatric patients was 72% with acceptable toxicity. Our results are comparable with the studies of other developed countries.