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A model for the mechanism of human topoisomerase I (1998)

L. Stewart ; M. R. Redinbo ; X. Qiu ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 279(5356): 1534-41.

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Publication Date: 1998-03-21

Description: The three-dimensional structure of a 70-kilodalton amino terminally truncated form of human topoisomerase I in complex with a 22-base pair duplex oligonucleotide, determined to a resolution of 2.8 angstroms, reveals all of the structural elements of the enzyme that contact DNA. The linker region that connects the central core of the enzyme to the carboxyl-terminal domain assumes a coiled-coil configuration and protrudes away from the remainder of the enzyme. The positively charged DNA-proximal surface of the linker makes only a few contacts with the DNA downstream of the cleavage site. In combination with the crystal structures of the reconstituted human topoisomerase I before and after DNA cleavage, this information suggests which amino acid residues are involved in catalyzing phosphodiester bond breakage and religation. The structures also lead to the proposal that the topoisomerization step occurs by a mechanism termed "controlled rotation."〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stewart, L -- Redinbo, M R -- Qiu, X -- Hol, W G -- Champoux, J J -- CA65656/CA/NCI NIH HHS/ -- GM16713/GM/NIGMS NIH HHS/ -- GM49156/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1998 Mar 6;279(5356):1534-41.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomolecular Structure Center and Department of Biological Structure, School of Medicine, University of Washington, Seattle, WA 98195-7742, USA. emerald_biostructures@rocketmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9488652" target="_blank"〉PubMed〈/a〉

Keywords: Amino Acid Sequence ; Arginine/chemistry/metabolism ; Binding Sites ; Catalysis ; Crystallography, X-Ray ; DNA/chemistry/*metabolism ; DNA Topoisomerases, Type I/*chemistry/*metabolism ; Humans ; Hydrogen Bonding ; *Models, Chemical ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/chemistry/metabolism ; *Protein Conformation ; Protein Structure, Secondary ; Tyrosine/chemistry/metabolism

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA (1998)

M. R. Redinbo ; L. Stewart ; P. Kuhn ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 279(5356): 1504-13.

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Publication Date: 1998-03-21

Description: Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient single-stranded break in duplex DNA and are vital for the processes of replication, transcription, and recombination. The crystal structures at 2.1 and 2.5 angstrom resolution of reconstituted human topoisomerase I comprising the core and carboxyl-terminal domains in covalent and noncovalent complexes with 22-base pair DNA duplexes reveal an enzyme that "clamps" around essentially B-form DNA. The core domain and the first eight residues of the carboxyl-terminal domain of the enzyme, including the active-site nucleophile tyrosine-723, share significant structural similarity with the bacteriophage family of DNA integrases. A binding mode for the anticancer drug camptothecin is proposed on the basis of chemical and biochemical information combined with these three-dimensional structures of topoisomerase I-DNA complexes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Redinbo, M R -- Stewart, L -- Kuhn, P -- Champoux, J J -- Hol, W G -- CA65656/CA/NCI NIH HHS/ -- GM49156/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1998 Mar 6;279(5356):1504-13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomolecular Structure Center and Department of Biological Structure, Box 357742, School of Medicine, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9488644" target="_blank"〉PubMed〈/a〉

Keywords: Antineoplastic Agents, Phytogenic/metabolism/pharmacology ; Binding Sites ; Camptothecin/analogs & derivatives/metabolism/pharmacology ; Crystallography, X-Ray ; DNA/chemistry/*metabolism ; DNA Topoisomerases, Type I/*chemistry/genetics/metabolism ; *DNA-Binding Proteins ; Homeodomain Proteins/chemistry ; Host Cell Factor C1 ; Humans ; Hydrogen Bonding ; Integrases/chemistry ; Models, Molecular ; Mutation ; Nucleic Acid Conformation ; Octamer Transcription Factor-1 ; Oligodeoxyribonucleotides/chemistry/metabolism ; *Protein Conformation ; Protein Structure, Secondary ; Recombinant Proteins/chemistry ; Transcription Factors/chemistry ; Tyrosine/chemistry/metabolism

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Structure of the heat shock protein chaperonin-10 of Mycobacterium leprae (1996)

S. C. Mande ; V. Mehra ; B. R. Bloom ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 271(5246): 203-7.

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Publication Date: 1996-01-12

Description: Members of the chaperonin-10 (cpn10) protein family, also called heat shock protein 10 and in Escherichia coli GroES, play an important role in ensuring the proper folding of many proteins. The crystal structure of the Mycobacterium leprae cpn10 (Ml-cpn10) oligomer has been elucidated at a resolution of 3.5 angstroms. The architecture of the Ml-cpn10 heptamer resembles a dome with an oculus in its roof. The inner surface of the dome is hydrophilic and highly charged. A flexible region, known to interact with cpn60, extends from the lower rim of the dome. With the structure of a cpn10 heptamer now revealed and the structure of the E. coli GroEL previously known, models of cpn10:cpn60 and GroEL:GroES complexes are proposed.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mande, S C -- Mehra, V -- Bloom, B R -- Hol, W G -- AI07118/AI/NIAID NIH HHS/ -- AI23545/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 1996 Jan 12;271(5246):203-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Structure, University of Washington, Seattle 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8539620" target="_blank"〉PubMed〈/a〉

Keywords: Amino Acid Sequence ; Chaperonin 10/*chemistry/metabolism ; Chaperonin 60/chemistry/metabolism ; Crystallography, X-Ray ; Models, Molecular ; Molecular Sequence Data ; Mycobacterium leprae/*chemistry ; *Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Sequence Alignment

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

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Structure Determination of the Human Protective Protein: Twofold Averaging Reveals the Three-Dimensional Structure of a Domain Which was Entirely Absent in the Initial Model (1996)

Rudenko, G. ; Bonten, E. ; d'Azzo, A. ; [et al.]

Copenhagen : International Union of Crystallography (IUCr)

Acta crystallographica 52 (1996), S. 923-936

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ISSN: 1399-0047

Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001

Topics: Chemistry and Pharmacology , Geosciences , Physics

Notes: Mutations in the human `protective protein' result in the human lysosomal storage disease galactosialidosis. The structure of the human `protective protein' has been determined using X-ray crystallography to a resolution of 2.2 Å. Initial phases were obtained from molecular replacement calculations. A very partial search model comprising 30% of the scattering mass, was constructed from the atomic model of the wheat serine carboxypeptidase. This truncated probe was used to find the position of two monomers in the asymmetric unit. Subsequently, `bootstrapping' cycles, consisting of twofold averaging and model expansion, retrieved the electron density for residues initially missing. In particular, it proved possible to add a domain (more than 110 residues) to the initial partial search model. In total, 314 residues per asymmetric unit were added to the 588 residues of the initial model. Factors contributing to our success are discussed.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1107/S0907444996004702

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Refined 3.2 Å structure of glycosomal holo glyceraldehyde phosphate dehydrogenase from Trypanosoma brucei brucei (1995)

Vellieux, F. M. D. ; Hajdu, J. ; Hol, W. G. J.

Copenhagen : International Union of Crystallography (IUCr)

Acta crystallographica 51 (1995), S. 575-589

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ISSN: 1399-0047

Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001

Topics: Chemistry and Pharmacology , Geosciences , Physics

Notes: The three-dimensional crystal structure of the enzyme glyceraldehyde phosphate dehydrogenase from the kinetoplastid Trypanosoma brucei brucei has been determined at 3.2 Å resolution from a 37% complete data set collected using the Laue method. The crystals used in the structure determination contain one and a half tetrameric enzyme molecules in the asymmetric unit, i.e. six identical subunits. Initial phasing was carried out by the method of molecular replacement using the refined coordinates of holo glyceraldehyde phosphate dehydrogenase from Bacillus stearothermophilus as a search model. The initial electron-density distribution, obtained from the molecular-replacement solution, was greatly improved by a procedure consisting of 36 cycles of iterative non-crystallographic density averaging. During the averaging procedure, the missing reflections (63% of the data) were gradually introduced as map-inversion structure factors. At completion of the procedure, the R-factor between averaged map-inversion amplitudes and observed structure-factor amplitudes was 19.0% for all data between 7.0 and 3.2 Å resolution, and that between the map-inversion amplitudes and later recorded structure-factor amplitudes was 41.9%. After model building into the resulting averaged electron-density map, refinement by molecular-dynamics procedures with X-PLOR provided the current model, which has an R-factor of 17.6% for 34 835 reflections between 7.0 and 3.2 Å resolution. The refined model, comprising 2735 protein atoms plus one NAD+ molecule and two sulfate ions per subunit, has r.m.s. deviations from ideality of 0.02 Å for bond lengths and 3.6° for bond angles. All subunits, located either within the tetrameric molecule or within the half tetramer present in the asymmetric unit, are related to each other by almost exact twofold symmetry. The overall structure of the glycosomal glyceraldehyde phosphate dehydrogenase subunit and its quaternary arrangement in the tetrameric molecule are similar to that of the enzyme of lobster and Bacillus stearothermophilus (with r.m.s. differences between equivalent Cα positions of 0.71 and 0.64 Å, respectively). The main differences between the structures is the presence of three insertions, plus the substitution of a β-strand by a short α-helix, both occurring at the surface of the glycosomal enzyme subunit.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1107/S0907444995003015

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Probing the Limits of the Molecular Replacement Method: the Case of Trypanosoma brucei Phosphoglycerate Kinase (1997)

Bernstein, B. E. ; Hol, W. G. J.

Copenhagen : International Union of Crystallography (IUCr)

Acta crystallographica 53 (1997), S. 756-764

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ISSN: 1399-0047

Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001

Topics: Chemistry and Pharmacology , Geosciences , Physics

Notes: It is of general interest to explore the limits of the molecular replacement method. Described here are the specifics of a successful molecular replacement structure determination in a difficult case: the X-ray crystal structure of a Trypanosoma brucei phosphoglycerate kinase (PGK) ternary complex. This ternary complex crystallizes with four 45 kDa subunits in the asymmetric unit, whereas the available search models were all monomers consisting of two distinct domains. Initial molecular replacement attempts using complete subunits were unsuccessful. Attributing this failure to a presumed change in the relative orientations of the N- and C-terminal phosphoglycerate kinase domains, a second attempt was made using each domain as an independent search model. In this way, two N-terminal and then two C-terminal domains could be oriented and positioned in the unit cell. On the basis of this result, a new search model containing both domains in the correct mutual orientation was created and used to identify the two remaining phosphoglycerate kinase subunits. The ability to successfully orient and position an N-terminal domain containing 8.4% of the scattering mass in the asymmetric unit was the key to this structure determination. Further investigations show that a truncated version of this search model containing 5.8% of the scattering mass would have been sufficient for this purpose. A retrospective analysis suggests that the effectiveness of this probe is enhanced by structural conservation, retained temperature factors and a disparity in the degree of order among the various subunits in the T. brucei PGK asymmetric unit. Based on these observations, 231 well ordered Cα atoms were selected from a single refined T. brucei PGK subunit and it was demonstrated that this collection of atoms, representing just 1.6% of the scattering mass, could be correctly oriented and positioned in the unit cell.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1107/S0907444997010214

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