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Bornyl diphosphate synthase: Structure and strategy for carbocation manipulation by a terpenoid cyclase
Structures of complexes with aza analogues of substrate and carbocation intermediates, as well as complexes with pyrophosphate and bornyl diphosphate, provide “snapshots” of the terpene cyclization cascade. Expand
Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells
The three-dimensional structure of the extracellular catalytic domain of human CA XII is determined by x-ray crystallographic methods and reveals a prototypical CA fold; however, two CA XII domains associate to form an isologous dimer, an observation that is confirmed by studies of the enzyme in solution. Expand
Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis
The crystal structure of LpxC from Aquifex aeolicus is reported, which reveals a new α+β fold reflecting primordial gene duplication and fusion, as well as a new zinc-binding motif, thereby representing a step toward the structure-based design of a potent, broad-spectrum antibacterial drug. Expand
AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies.
AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies and the synergistic combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. Expand
Crystal structures of the methane monooxygenase hydroxylase from Methylococcus capsulatus (Bath): Implications for substrate gating and component interactions
The crystal structure of the nonheme iron‐containing hydroxylase component of methane monooxygenase hydroxylase (MMOH) from Methylococcus capsulatus (Bath) has been solved in two crystal forms, oneExpand
Mechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylase.
The results suggest that the native state of this metallohydrolase may contain a pentacoordinate zinc ion, which contrasts with the native states of archetypical zinc hydrolases such as thermolysin and carboxypeptidase A. Expand
Crystal structures of the soluble methane monooxygenase hydroxylase from Methylococcus capsulatus (Bath) demonstrating geometrical variability at the dinuclear iron active site.
Crystal structures of MMOH from Methylococcus capsulatus are investigated in an effort to delineate the range of possible motions at the MMOH active site and to identify hydrogen-bonding interactions that may be important in understanding catalysis by the enzyme. Expand
Xenon and halogenated alkanes track putative substrate binding cavities in the soluble methane monooxygenase hydroxylase.
Results indicate that hydrophobic species bind preferentially in preexisting cavities in MMOH and support the hypothesis that such cavities may play a functional role in sequestering and enhancing the availability of the physiological substrates for reaction at the active site. Expand
Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors.
This work reports the discovery of compound 82 as a potent dual inhibitor of PI3K and mTOR, which exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability and demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models. Expand
Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
A series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis are developed. Expand