The peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone has recently been withdrawn from the European market and its use has been restricted in the US due to its undesirable effects which were considered to outweigh its benefits. Literature indicates that there are two agonist bound conformations of the PPARγ as exemplified by its binding to rosiglitazone (PDB ID; 1FM...

Targeting the protein kinase ATP-binding pocket provides a significant opportunity for the treatment of disease. Recent studies have revealed a central activity-independent role for nucleotide pocket occupation in the allosteric behaviour of diverse kinases. Regulation of nucleotide pocket conformation with either nucleotides or ATP competitive inhibitors has revealed an added dimension to the ...

A binding pocket for thyrotropin-releasing hormone (TRH) within the transmembrane helices of the TRH receptor type 1 (TRH-R1) has been identified based on experimental evidence and computer simulations. To determine the binding site for a competitive inverse agonist, midazolam, three of the four residues that directly contact TRH and other residues that restrain TRH-R1 in an inactive conformati...

Blockade of the angiotensin (ANG) II receptor type 1 (AT(1)R) with angiotensin receptor blockers (ARBs) is widely used in the treatment of hypertension. However, ARBs are variably effective in reducing blood pressure, likely due, in part, to polymorphisms in the ARB binding pocket of the AT(1)R. Therefore, we need a better understanding of variations/polymorphisms that alter binding of ARBs in ...

A flavin-dependent group E monooxygenase ("GEM”) has been characterized by crystal-structure analysis, computational and kinetic studies to reveal substrate binding mechanistic details for this class of enzymes the first time. Based on these data, Dirk Tischler, Norbert Sträter, co-workers redesigned pocket synthesize chiral epoxides sulfoxides with high stereoselectivity, a true treasure molec...

The phosphorylation-dependent anchorage of retinoblastoma protein Rb in the nucleus is essential for its function. We show that its pocket C domain is both necessary and sufficient for nuclear anchorage by transiently expressing green fluorescent protein (GFP) chimeras of Rb fragments in tissue culture cells and by extracting the cells with hypotonic solutions. Solid phase binding assays using ...

Eg5, a mitotic kinesin exclusively involved in the formation and function of the mitotic spindle has attracted interest as an anticancer drug target. Eg5 is co-crystallized with several inhibitors bound to its allosteric binding pocket. Each of these occupies a pocket formed by loop 5/helix alpha2 (L5/alpha2). Recently designed inhibitors additionally occupy a hydrophobic pocket of this site. T...

Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-...

The high level of conservation in ATP-binding sites of protein kinases increasingly demandsthe quest to find selective inhibitors with little cross reactivity. Kinase kinases are a recently discovered group of Kinases found to be involved in several mitotic events. These proteins represent attractive targets for cancer therapy with several small molecule inhibitors undergoing different ph...