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63 items found (0 items not approved), displaying 61 to 63.[First/Prev] 1, 2, 3, 4, 5, 6, 7 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	The CDK9 C-helix exhibits conformational plasticity that may explain the selectivity of CAN508 Sonja Baumli , Alison Hole , Martin E. M. Noble , Jane A. Endicott Acs Chemical Biology 7 (5), 811 - 816 DOI: 10.1021/cb2004516 PMID: 22292676 Open Access Show Abstract ▼ Abstract: CDK9 is the kinase of positive transcription elongation factor b and facilitates the transition of paused RNA polymerase II to processive transcription elongation. CDK9 is a validated target for the treatment of cancer, cardiac hypertrophy, and human immunodeficiency virus. Here we analyze different CDK9/cyclin T variants to identify a form of the complex amenable to use in inhibitor design. To demonstrate the utility of this system, we have determined the crystal structures of CDK9/cyclin T and CDK2/cyclin A bound to the CDK9-specific inhibitor CAN508. Comparison of the structures reveals CDK9-specific conformational changes and identifies a CDK9-specific hydrophobic pocket, adjacent to the áC-helix. By comparison with a previously published structure of CDK9/cyclin T/human immunodeficiency virus TAT we find that the CDK9 áC-helix has a degree of conformational variability that has the potential to be exploited for inhibitor design.	May 2012
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Targeting the Hsp90 molecular chaperone with novel macrolactams. synthesis, structural, binding, and cellular studies James E. H. Day , Swee Y. Sharp , Martin G. Rowlands , Wynne Aherne , Angela Hayes , Florence I. Raynaud , William Lewis , S. Mark Roe , Chrisostomos Prodromou , Laurence H. Pearl , Paul Workman , Christopher J. Moody Acs Chemical Biology 6 (12), 1339 - 1347 DOI: 10.1021/cb200196e PMID: 21932796 Diamond Proposal Number(s): [6385] Show Abstract ▼ Abstract: A series of resorcylic acid macrolactams, nitrogen analogues of the naturally occurring macrolactone radicicol, have been prepared by chemical synthesis and evaluated as inhibitors of heat shock protein 90 (Hsp90), an emerging attractive target for novel cancer therapeutic agents. The synthesis involves, as key steps, ring opening of an isocoumarin intermediate, followed by a ring- closing metathesis reaction to form the macrocycle. Subsequent manipulation of the ester group into a range of amides allows access to a range of new macrolactams following deprotection of the two phenolic groups. These new resorcylic acid lactams exhibit metabolic stability greater than that of related lactone counterparts, while co-crystallization of three macrolactams with the N-terminal domain ATP site of Hsp90 conforms that they bind in a similar way to the natural product radicicol and to our previous synthetic lactone analogues. Interestingly, however, in the case of the N- benzylamide, additional binding to a hydrophobic pocket of the protein was observed. In biological assays, the new macrocyclic lactams exhibit a biological pro\ufb01le equivalent or superior to that of the related lactones and show the established molecular signature of Hsp90 inhibitors in human colon cancer cells.	Dec 2011
I03-Macromolecular Crystallography	Structural basis of the radicicol resistance displayed by a fungal Hsp90 Chrisostomos Prodromou , James M. Nuttall , Stefan H. Millson , Tiow-Suan Sim , Doreen Tan , Paul Workman , Laurence H. Pearl , Peter W. Piper , S. Mark Roe Acs Chemical Biology 4 (4), 289297 DOI: 10.1021/cb9000316 PMID: 19236053 Show Abstract ▼ Abstract: Heat shock protein 90 (Hsp90) is a promising cancer drug target, as multiple oncogenic proteins are destabilized simultaneously when it loses its activity in tumor cells. Highly selective Hsp90 inhibitors, including the natural antibiotics geldanamycin (GdA) and radicicol (RAD), inactivate this essential molecular chaperone by occupying its nucleotide binding site. Often cancer drug therapy is compromised by the development of resistance, but a resistance to these Hsp90 inhibitors should not arise readily by mutation of those amino acids within Hsp90 that facilitate inhibitor binding, as these are required for the essential ATP binding/ATPase steps of the chaperone cycle and are tightly conserved. Despite this, the Hsp90 of a RAD-producing fungus is shown to possess an unusually low binding affinity for RAD but not GdA. Within its nucleotide binding site a normally conserved leucine is replaced by isoleucine, though the chaperone ATPase activity is not severely affected. Inserted into the Hsp90 of yeast, this conservative leucine to isoleucine substitution recreated this lowered affinity for RAD in vitro. It also generated a substantially enhanced resistance to RAD in vivo. Co-crystal structures reveal that the change to isoleucine is associated with a localized increase in the hydration of an Hsp90-bound RAD but not GdA. To the best of our knowledge, this is the first demonstration that it is possible for Hsp90 inhibitor resistance to arise by subtle alteration to the structure of Hsp90 itself.	Feb 2009

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