5g2b: Difference between revisions

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 ==Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-008==
-<StructureSection load='5g2b' size='340' side='right' caption='[[5g2b]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
+<StructureSection load='5g2b' size='340' side='right'caption='[[5g2b]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5g2b]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5G2B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5G2B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5g2b]] 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=5G2B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5G2B FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LQY:N-(2-amino-2-oxoethyl)-5-[(4aR,8aS)-3-cycloheptyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl]-2-methoxy[1,1-biphenyl]-4-carboxamide'>LQY</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.83&#8491;</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=5g2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g2b OCA], [http://pdbe.org/5g2b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5g2b RCSB], [http://www.ebi.ac.uk/pdbsum/5g2b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5g2b ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LQY:N-(2-amino-2-oxoethyl)-5-[(4aR,8aS)-3-cycloheptyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl]-2-methoxy[1,1-biphenyl]-4-carboxamide'>LQY</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=5g2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g2b OCA], [https://pdbe.org/5g2b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5g2b RCSB], [https://www.ebi.ac.uk/pdbsum/5g2b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5g2b ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/Q8WQX9_9TRYP Q8WQX9_9TRYP]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent ( Ki = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC50 = 5.5 and 6.7 muM, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis.
+Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.,Blaazer AR, Singh AK, de Heuvel E, Edink E, Orrling KM, Veerman JJN, van den Bergh T, Jansen C, Balasubramaniam E, Mooij WJ, Custers H, Sijm M, Tagoe DNA, Kalejaiye TD, Munday JC, Tenor H, Matheeussen A, Wijtmans M, Siderius M, de Graaf C, Maes L, de Koning HP, Bailey DS, Sterk GJ, de Esch IJP, Brown DG, Leurs R J Med Chem. 2018 May 1. doi: 10.1021/acs.jmedchem.7b01670. PMID:29672041<ref>PMID:29672041</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 5g2b" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
-[[Category: Anthonyrajah, E S]]
+[[Category: Large Structures]]
-[[Category: Brown, D G]]
+[[Category: Trypanosoma brucei]]
-[[Category: Singh, A K]]
+[[Category: Anthonyrajah ES]]
-[[Category: African trypanosomiasis]]
+[[Category: Brown DG]]
-[[Category: Hydrolase]]
+[[Category: Singh AK]]
-[[Category: Parasitic pde]]
-[[Category: Sleeping sickness]]