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Homology model of the human tRNA splicing ligase RtcB

Journal article
Authors A. Nandy
Patricia Saenz-Mendez
A. M. Gorman
A. Samali
Leif A Eriksson
Published in Proteins-Structure Function and Bioinformatics
Volume 85
Issue 11
Pages 1983-1993
ISSN 0887-3585
Publication year 2017
Published at Department of Chemistry and Molecular Biology
Pages 1983-1993
Language en
Keywords active site, homology modeling, HSPC117, Mn coordination, RtcB, tRNA ligase, XBP1s, unfolded protein response, sequential 2',3'-cyclic phosphodiesterase, umbrella sampling analysis, molecular-dynamics, messenger-rna, anticodon, nuclease, force-field, ligation, 3'-phosphate, cancer
Subject categories Biochemistry and Molecular Biology


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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