6ezf

PDE2 in complex with molecule 5

spinqualitylabelsall models 6ezf, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ezf is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: C6Z, GOL, MG, NA, SO4, ZN Activity: 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphodiesterase

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