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Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte
It is found that cGMP passes through gap junctions into the oocyte, where it inhibits the hydrolysis of cAMP by the phosphodiesterase PDE3A, and causes a decrease in oocyte cAMP, leading to the resumption of meiosis. Expand
Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13
A molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs is provided. Expand
Structures of the N-terminal and middle domains of E. coli Hsp90 and conformation changes upon ADP binding.
The crystal structures of the unliganded and ADP bound fragments containing the N-terminal and middle domains of HtpG, an E. coli Hsp90 chaperone, are reported here, suggesting somewhat different mechanisms for the ATPase superfamily. Expand
Crystal structure of DJ‐1/RS and implication on familial Parkinson's disease 1
The structure shows that Leu166 positions in the middle of a helix and thus predicts that the L166P mutation will bend theHelix and impact the dimerization of DJ‐1, leading to the familial Parkinson's disease caused by the single L166p mutation. Expand
Structural basis for an inositol pyrophosphate kinase surmounting phosphate crowding.
This work obtained crystal structures of the kinase domain of human PPIP5K2 complexed with nucleotide cofactors and either substrates, product or a MgF(3)(-) transition-state mimic and described the enzyme's conformational dynamics, its unprecedented topological presentation of nucleotide and inositol phosphate, and the charge balance that facilitates partly associative in-line phosphoryl transfer. Expand
Multiple Conformations of Phosphodiesterase-5
Phosphodiesterase-5 (PDE5) is the target for sildenafil, vardenafil, and tadalafil, which are drugs for treatment of erectile dysfunction and pulmonary hypertension. We report here the crystalExpand
Crystal structure of the Leishmania major phosphodiesterase LmjPDEB1 and insight into the design of the parasite‐selective inhibitors
The kinetic characterization of the LmjPDEB1 catalytic domain and its crystal structure as a complex with 3‐isobutyl‐1‐methylxanthine (IBMX) at 1.55 Å resolution shows structure particularity might be useful for the development of parasite‐selective inhibitors for the treatment of leishmaniasis. Expand
Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.
The authors' analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors, and reveal significant conformational differences in the active sites of Pde4B and PDE 4D. Expand
Multiple Elements Jointly Determine Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases 4 and 7*
The crystal structure of PDE7A1 catalytic domain in complex with non-selective inhibitor 3-isobutyl-1-methylxanthine and kinetic analysis on the mutants of Pde6A1 and PDE4D2 suggest at least three elements play critical roles in inhibitor selectivity: the conformation and position of an invariant glutamine, the natures of scaffolding residues, and residues that alter shape and size of the binding pocket. Expand
Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure.
The unliganded TbrPDEB1 X-ray structure was subjected to a structure-based in silico screening approach that combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method and identified six novel Tbr PDEB1 inhibitors with IC50 values of 10-80 μM, which may be further optimized as potential selective T brPDEB inhibitors. Expand