6ezf: Difference between revisions
New page: '''Unreleased structure''' The entry 6ezf is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==PDE2 in complex with molecule 5== | ||
<StructureSection load='6ezf' size='340' side='right'caption='[[6ezf]], [[Resolution|resolution]] 1.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ezf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EZF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EZF 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]] 1.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C6Z:6-[(2,4-dichlorophenyl)methyl]pyridazine-3-thiol'>C6Z</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6ezf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ezf OCA], [https://pdbe.org/6ezf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ezf RCSB], [https://www.ebi.ac.uk/pdbsum/6ezf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ezf ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PDE2A_HUMAN PDE2A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.<ref>PMID:15938621</ref> <ref>PMID:19828435</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A congeneric series of 21 phosphodiesterase 2 (PDE2) inhibitors are reported. Crystal structures show how the molecules can occupy a 'top-pocket' of the active site. Molecules with small substituents do not enter the pocket, a critical leucine (Leu770) is closed and water molecules are present. Large substituents enter the pocket, opening the Leu770 conformation and displacing the waters. We also report an X-ray structure revealing a new conformation of the PDE2 active site domain. The relative binding affinities of these compounds were studied with free energy perturbation (FEP) methods and it represents an attractive real-world test case. In general, the calculations could predict the energy of small-to-small, or large-to-large molecule perturbations. However, accurately capturing the transition from small-to-large proved challenging. Only when using alternative protein conformations did results improve. The new X-ray structure, along with a modelled dimer, conferred stability to the catalytic domain during the FEP molecular dynamics (MD) simulations, increasing the convergence and thereby improving the prediction of DeltaDeltaG of binding for some small-to-large transitions. In summary, we found the most significant improvement in results when using different protein structures, and this data set is useful for future free energy validation studies. | |||
Predicting Binding Free Energies of PDE2 Inhibitors. The Difficulties of Protein Conformation.,Perez-Benito L, Keranen H, van Vlijmen H, Tresadern G Sci Rep. 2018 Mar 20;8(1):4883. doi: 10.1038/s41598-018-23039-5. PMID:29559702<ref>PMID:29559702</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6ezf" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Keraenen H]] | |||
[[Category: Perez-Benito L]] | |||
[[Category: Tresadern G]] | |||
[[Category: Van Vlijmen H]] | |||
Latest revision as of 15:23, 9 May 2024
PDE2 in complex with molecule 5PDE2 in complex with molecule 5
Structural highlights
FunctionPDE2A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[1] [2] Publication Abstract from PubMedA congeneric series of 21 phosphodiesterase 2 (PDE2) inhibitors are reported. Crystal structures show how the molecules can occupy a 'top-pocket' of the active site. Molecules with small substituents do not enter the pocket, a critical leucine (Leu770) is closed and water molecules are present. Large substituents enter the pocket, opening the Leu770 conformation and displacing the waters. We also report an X-ray structure revealing a new conformation of the PDE2 active site domain. The relative binding affinities of these compounds were studied with free energy perturbation (FEP) methods and it represents an attractive real-world test case. In general, the calculations could predict the energy of small-to-small, or large-to-large molecule perturbations. However, accurately capturing the transition from small-to-large proved challenging. Only when using alternative protein conformations did results improve. The new X-ray structure, along with a modelled dimer, conferred stability to the catalytic domain during the FEP molecular dynamics (MD) simulations, increasing the convergence and thereby improving the prediction of DeltaDeltaG of binding for some small-to-large transitions. In summary, we found the most significant improvement in results when using different protein structures, and this data set is useful for future free energy validation studies. Predicting Binding Free Energies of PDE2 Inhibitors. The Difficulties of Protein Conformation.,Perez-Benito L, Keranen H, van Vlijmen H, Tresadern G Sci Rep. 2018 Mar 20;8(1):4883. doi: 10.1038/s41598-018-23039-5. PMID:29559702[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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