20 research outputs found
Hsp90 inhibitors.
<p>Chemical representation of the compounds co-crystallized with <i>T. brucei</i> Hsp83 NTD and the non- commercially available compounds used in this study. All the compounds are listed in the supplementary material (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002492#pntd.0002492.s002" target="_blank">Fig. S2</a>).</p
Structural superposition of <i>T. brucei</i> Hsp83 NTD complexes.
<p>(<b><sup>*</sup></b>) Root mean square deviation (r.m.s.d.) values in Ã… for all atoms superposition (residues 1 to 206). R.m.s.d. between non-crystallographic symmetry (NCS) mates is shown in italic.</p
Thermal shift assay results and thermodynamic parameters of <i>T. brucei</i> Hsp83 NTD interactions with inhibitors.
<p>(A) The Δ<i>T</i><sub>m</sub> values obtained by DSF are presented in this bar representation for a subset of the Hsp90 inhibitors tested. The DSF results for all compounds tested are available as supplementary material. (B) Binding Interactions Average values for Δ<i>G</i>, Δ<i>H</i>, -<i>T</i>Δ<i>S</i> are given for protein-compound interactions measured by ITC. The Δ<i>T</i><sub>m</sub> values derived from DSF studies are also indicated. The raw ITC graphs are available as a supplementary material.</p
<i>T. brucei</i> Hsp83 NTD affinity<sup>*</sup> and parasite growth inhibition measurements.
<p>(<b><sup>*</sup></b>)Affinity measurements by ITC and DSF methods are reported.</p><p><b><i>a</i></b>) Human Hsp90α; <b><i>b</i></b>) Human Hsp90β; <b><i>c</i></b>) Human TRAP-1; <b><i>d</i></b>) Yeast Hsp83. N.D. – not determined.</p
Crystal structure of <i>T. brucei</i> Hsp83 NTD.
<p>(A) A cartoon representation of the parasitic protein, the nucleotide lid region is highlighted in magenta, α-helices 3 and 4 are shown in light green. The ATP mimetic shown to indicate the position of the nucleotide binding site was derived from the <i>L. major</i> complex structure (PBD entry 3H80). (B) NTDs structural overlay between <i>Tb</i>Hsp83 (cyan) and human αHsp90 (yellow – PDB entry 3QDD). (C) Structural overlay of <i>Tb</i>Hsp83 NTD inhibitor complexes. Two orthogonal views of ribbon representations of the three complexes and the compounds are indicated as sticks. The structures are colored as follows, compound <b>1</b> complex – cyan; thienopyrimidine derivative compound <b>3</b> – green; benzamidine derivative compound 4 – brown.</p
Protein-ligand interaction maps of <i>T. brucei</i> Hsp83 NTD complexes.
<p>The Hsp83 NTD-AMPPNP interaction map was derived from the <i>L. major</i> complex structure (PDB entry 3U67). The gray region represents the adenosine binding pocket; additional residues in common with the nucleotide analogue complex structure are highlighted in blue.</p
<i>T. brucei</i> Hsp83 nucleotide binding pocket.
<p>Surface representation in the NTD binding site for the <i>Trypanosoma</i> complex structures (compound <b>1</b> complex – cyan; thienopyrimidine derivative compound <b>3</b> – green; benzamidine derivative compound <b>4</b> – brown). The nucleotide binding pocket of <i>L. major</i> (PDB code 3H80 – Magenta) is shown for comparison purposes.</p
Summary of crystallographic parameters and model refinement statistics for <i>T. brucei</i> Hsp83 NTD complexes.
<p>Summary of crystallographic parameters and model refinement statistics for <i>T. brucei</i> Hsp83 NTD complexes.</p
ATPase kinetic parameters for <i>T. brucei</i> Hsp83 and reported activities for other Hsp90s<sup>*</sup>.
<p>(<sup>*</sup>) values ± standard deviation.</p
<i>T. brucei</i> Hsp83 NTD structural changes.
<p>Cartoon representation of α-helices 1, 3 and 4, and the lid region from the Hsp83 in complex with different compounds (compound <b>1</b> complex – cyan; thienopyrimidine derivative compound <b>3</b> – green; benzamidine derivative compound <b>4</b> – brown; and <i>L. major</i> with AMPPNP – magenta). Side chains of residues Asn90 and Asn91 are indicated in sticks, also the nucleotide is indicated as yellow dots to illustrate the location of binding site.</p