1mx2
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(New page: 200px<br /> <applet load="1mx2" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mx2, resolution 2.25Å" /> '''Structure of F71N m...)
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Revision as of 16:09, 12 November 2007
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Structure of F71N mutant of p18INK4c
Overview
p18(INK4c) is a member of the INK4 family of proteins that regulate the, G(1) to S cell cycle transition by binding to and inhibiting the pRb, kinase activity of cyclin-dependent kinases 4 and 6. The p16(INK4a) member, of the INK4 protein family is altered in a variety of cancers and, structure-function studies of the INK4 proteins reveal that the vast, majority of missense tumor-derived p16(INK4a) mutations reduce protein, thermodynamic stability. Based on this observation, we used p18(INK4c) as, a model to test the proposal that INK4 proteins with increased stability, might have enhanced cell cycle inhibitory activity. Structure-based, mutagenesis was used to prepare p18(INK4c) mutant proteins with a, predicted increase in stability. Using this approach, we report the, generation of three mutant p18(INK4C) proteins, F71N, F82Q, and F92N, with, increased stability toward thermal denaturation of which the F71N mutant, also showed an increased stability to chemical denaturation. The x-ray, crystal structures of the F71N, F82Q, and F92N p18INK4C mutant proteins, were determined to reveal the structural basis for their increased, stability properties. Significantly, the F71N mutant also showed enhanced, CDK6 interaction and cell cycle inhibitory activity in vivo, as measured, using co-immunoprecipitation and transient transfection assays, respectively. These studies show that a structure-based approach to, increase the thermodynamic stability of INK4 proteins can be exploited to, prepare more biologically active molecules with potential applications for, the development of molecules to treat p16(INK4a)-mediated cancers.
About this Structure
1MX2 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure-based design of p18INK4c proteins with increased thermodynamic stability and cell cycle inhibitory activity., Venkataramani RN, MacLachlan TK, Chai X, El-Deiry WS, Marmorstein R, J Biol Chem. 2002 Dec 13;277(50):48827-33. Epub 2002 Oct 4. PMID:12370184
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