6rb6: Difference between revisions
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==Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-053== | |||
<StructureSection load='6rb6' size='340' side='right'caption='[[6rb6]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6rb6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RB6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RB6 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=JX2:3-[5-[(4~{a}~{R},8~{a}~{S})-3-cycloheptyl-4-oxidanylidene-4~{a},5,8,8~{a}-tetrahydrophthalazin-1-yl]-2-methoxy-phenyl]-~{N}-(furan-2-ylmethyl)prop-2-ynamide'>JX2</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6rb6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rb6 OCA], [https://pdbe.org/6rb6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rb6 RCSB], [https://www.ebi.ac.uk/pdbsum/6rb6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rb6 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q8WQX9_9TRYP Q8WQX9_9TRYP] | |||
<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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Brown | <div class="pdbe-citations 6rb6" style="background-color:#fffaf0;"></div> | ||
[[Category: Singh | |||
==See Also== | |||
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Trypanosoma brucei]] | |||
[[Category: Brown DG]] | |||
[[Category: Singh AK]] | |||
Latest revision as of 15:18, 24 January 2024
Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-053Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-053
Structural highlights
FunctionPublication Abstract from PubMedInhibitors 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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