View source for 6gxq


==Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-1335==
<StructureSection load='6gxq' size='340' side='right'caption='[[6gxq]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6gxq]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_(trypanozoon)_brucei Trypanosoma (trypanozoon) brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GXQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GXQ FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FFZ:3-[5-[(4aR,8aS)-4-OXIDANYLIDENE-3-PROPAN-2-YL-4a,5,8,8a-TETRAHYDROPHTHALAZIN-1-YL]-2-METHOXY-PHENYL]-N-(PHENYLMETHYL)PROP-2-YNAMIDE'>FFZ</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDEB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5691 Trypanosoma (Trypanozoon) brucei])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6gxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gxq OCA], [http://pdbe.org/6gxq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gxq RCSB], [http://www.ebi.ac.uk/pdbsum/6gxq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gxq ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2).,de Heuvel E, Singh AK, Boronat P, Kooistra AJ, van der Meer T, Sadek P, Blaazer AR, Shaner NC, Bindels DS, Caljon G, Maes L, Sterk GJ, Siderius M, Oberholzer M, de Esch IJP, Brown DG, Leurs R Bioorg Med Chem. 2019 Jul 5. pii: S0968-0896(19)30790-4. doi:, 10.1016/j.bmc.2019.06.026. PMID:31378593<ref>PMID:31378593</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6gxq" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Brown, D G]]
[[Category: Singh, A K]]
[[Category: African trypanosomiasis]]
[[Category: Hydrolase]]
[[Category: Parasitic phosphodiesterase]]
[[Category: Sleeping sickness]]