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Bornyl diphosphate synthase: Structure and strategy for carbocation manipulation by a terpenoid cyclase
- D. Whittington, M. Wise, M. Urbanský, R. Coates, R. Croteau, D. Christianson
- ChemistryProceedings of the National Academy of Sciences…
- 13 November 2002
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.
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.
Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells
- D. Whittington, A. Waheed, D. Christianson
- Chemistry, BiologyProceedings of the National Academy of Sciences…
- 7 August 2001
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.
Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis
- D. Whittington, K. Rusche, Hyunshun Shin, C. Fierke, D. Christianson
- Biology, ChemistryProceedings of the National Academy of Sciences…
- 20 June 2003
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.
Crystal structures of the methane monooxygenase hydroxylase from Methylococcus capsulatus (Bath): Implications for substrate gating and component interactions
- A. Rosenzweig, H. Brandstetter, D. Whittington, P. Nordlund, S. Lippard, C. Frederick
- 1 October 1997
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, one…
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.
Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors.
- B. Lanman, Jennifer R. Allen, V. Cee
- Biology, ChemistryJournal of medicinal chemistry
- 10 December 2019
Structural-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond, and biopharmaceutical optimization of the resulting leads culminated in the identified AMG 510.
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.
Mechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylase.
- H. A. Gennadios, D. Whittington, Xuechen Li, C. Fierke, D. Christianson
- 4 July 2006
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.
The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase*
- L. Epstein, Hao Chen, R. Emkey, D. Whittington
- Biology, ChemistryThe Journal of Biological Chemistry
- 29 August 2012
Crystal structures of the ALK kinase domain containing the F1174L and R1275Q mutations are reported, which illustrate a different series of activation loop conformations than has been observed in previous ALK crystal structures and provide insight into the activating nature of the R 1275Q mutation.