%0 Conference Proceedings %B Proceedings of the National Academy of Sciences of the United States of America %D 2011 %T Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step %A Kamil Steczkiewicz %A Michael T. Zimmermann %A Mateusz Kurcinski %A Benjamin A. Lewis %A Drena Dobbs %A Andrzej Kloczkowski %A Robert L. Jernigan %A Andrzej Koliński %A Krzysztof Ginalski %K Amino Acid %K Amino Acid Sequence %K Binding Sites %K Binding Sites: genetics %K Catalytic Domain %K Computer Simulation %K DNA %K DNA: chemistry %K DNA: genetics %K DNA: metabolism %K Humans %K Kinetics %K Models %K Molecular %K Molecular Sequence Data %K Nucleic Acid Conformation %K Nucleic Acid Heteroduplexes %K Nucleic Acid Heteroduplexes: chemistry %K Nucleic Acid Heteroduplexes: genetics %K Nucleic Acid Heteroduplexes: metabolism %K Polymerization %K Protein Binding %K Protein Structure %K RNA %K RNA: chemistry %K RNA: genetics %K RNA: metabolism %K Secondary %K Sequence Homology %K Telomerase %K Telomerase: chemistry %K Telomerase: genetics %K Telomerase: metabolism %K Telomere %K Telomere: chemistry %K Telomere: genetics %K Telomere: metabolism %K Tertiary %X Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the "end-replication" problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNADNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design. %B Proceedings of the National Academy of Sciences of the United States of America %V 108 %P 9443–8 %8 jun %G eng %U http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3111281&tool=pmcentrez&rendertype=abstract %R 10.1073/pnas.1015399108 %0 Journal Article %J The Journal of Chemical Physics %D 1987 %T Monte Carlo studies on the long time dynamic properties of dense cubic lattice multichain systems. II. Probe polymer in a matrix of different degrees of polymerization %A Andrzej Koliński %A Jeffrey Skolnick %A Robert Yaris %K Chains %K Computerized Simulation %K dynamics %K Liquid Structure %K Matrix Isolation %K Melts %K Monte Carlo Method %K Polymerization %K Polymers %X The dynamics of a probe chain consisting of nP =100 segments in a matrix of chains of length of nM=50 up to nM=800 at a total volume fraction of polymer ϕ=0.5 have been simulated by means of cubic lattice Monte Carlo dynamics. The diffusion coefficient of the probe chain over the range of nM under consideration decreases by about 30%, a behavior rather similar to that seen in real melts of very long chains. Furthermore, the analysis of the probe chain motion shows that the mechanism of motion is not reptation‐like and that the cage effect of the matrix is negligible. That is, the local fluctuations of the topological constraints imposed by the long matrix chains (even for nM=800) are sufficiently large to provide for essentially isotropic, but somewhat slowed down, motion of the probe, nP =100, chains relative to the homopolymer melt. The results of these MC experiments are discussed in the context of theoretical predictions and experimental findings for related systems. %B The Journal of Chemical Physics %V 86 %P 7174–7180 %G eng %U http://link.aip.org/link/JCPSA6/v86/i12/p7174/s1 %R 10.1063/1.452367