 |
|
|
 |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
366 a.a.
_MG
Key reference
DOI no: 10.1074/jbc.M506520200 J Biol Chem 280:37041-37047 (2005) PubMed id: 16100112
Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase. H.Wei, A.J.Ruthenburg, S.K.Bechis, G.L.Verdine. ABSTRACT
Type IIA DNA topoisomerases play multiple essential roles in the management of higher-order DNA structure, including modulation of topological state, chromosome segregation, and chromatin condensation. These diverse physiologic functions are all accomplished through a common molecular mechanism, wherein the protein catalyzes transient cleavage of a DNA duplex (the G-segment) to yield a double-stranded gap through which another duplex (the T-segment) is passed. The overall process is orchestrated by the opening and closing of molecular "gates" in the topoisomerase structure, which is regulated by ATP binding, hydrolysis, and release of ADP and inorganic phosphate. Here we present two crystal structures of the ATPase domain of human DNA topoisomerase IIalpha in different nucleotide-bound states. Comparison of these structures revealed rigid-body movement of the structural modules within the ATPase domain, suggestive of the motions of a molecular gate.
Selected figure(s)
Figure 1.
FIGURE 1. Overall structure of the 46-kDa ATPase domain of human topoisomerase II(HT2ATPase) (residues 29-428) bound to AMPPNP (A-C) and ADP (D-F). A and D, ribbon drawings emphasizing the modularity of the protein structure. Each of the four modules in the HT2ATPase homodimer is colored individually: blue and cyan, ATPase modules; magenta and peach, transducer modules. One protomer of HT2ATPase is blue and magenta; the other is cyan and peach. Asterisks denote the
-hairpin motif, unique to eukaryotic Topo II enzymes, which forms the upper end of the DNA channel. B and E, surface representation in the same orientation as A and D, with the
Figure 2.
FIGURE 2. Analysis of nucleotide-dependent domain movement in HT2ATPase. A, least-squares superposition of the two protomers in the asymmetric unit of the AMPPNP structure. B, superposition of the four protomers in the asymmetric unit of the ADP structure. C, superposition of the dimers of the AMPPNP (blue) and ADP (yellow) structures. The magnitude of domain rotation and translation is indicated. Red X indicates the approximate pivot point for rigid-body rotation. D and E, superposition of the individual (D) nucleotide-binding and (E) transducer modules in the AMPPNP structure and ADP structure (coloring as in C).The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 37041-37047) copyright 2005. Figures were selected by an automated process.
Literature references that cite this PDB file's key reference
PubMed id Reference
19603203 C.E.Cassidy, and W.N.Setzer (2010).
Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis.J Mol Model, 16, 311-326.
19377505 J.L.Nitiss (2009).
DNA topoisomerase II and its growing repertoire of biological functions.Nat Rev Cancer, 9, 327-337.
19128485 P.Chène, J.Rudloff, J.Schoepfer, P.Furet, P.Meier, Z.Qian, J.M.Schlaeppi, R.Schmitz, and T.Radimerski (2009).
Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue.BMC Chem Biol, 9, 1.
19155278 T.R.Collins, G.G.Hammes, and T.S.Hsieh (2009).
Analysis of the eukaryotic topoisomerase II DNA gate: a single-molecule FRET and structural perspective.Nucleic Acids Res, 37, 712-720.
18755053 A.J.Schoeffler, and J.M.Berger (2008).
DNA topoisomerases: harnessing and constraining energy to govern chromosome topology.Q Rev Biophys, 41, 41.
18403371 F.Mueller-Planitz, and D.Herschlag (2008).
Coupling between ATP binding and DNA cleavage by DNA topoisomerase II: A unifying kinetic and structural mechanism.J Biol Chem, 283, 17463-17476.
17603498 K.D.Corbett, P.Benedetti, and J.M.Berger (2007).
Holoenzyme assembly and ATP-mediated conformational dynamics of topoisomerase VI.Nat Struct Mol Biol, 14, 611-619.
PDB code: 2q2e
16549872 K.L.Gilroy, C.Leontiou, K.Padget, J.H.Lakey, and C.A.Austin (2006).
mAMSA resistant human topoisomerase IIbeta mutation G465D has reduced ATP hydrolysis activity.Nucleic Acids Res, 34, 1597-1607. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
 |