Publications by authors named "Derek G Rudge"

2 Publications

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mTOR kinase structure, mechanism and regulation.

Nature 2013 May 1;497(7448):217-23. Epub 2013 May 1.

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.
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http://dx.doi.org/10.1038/nature12122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512754PMC
May 2013

Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.

Science 2011 Jul;333(6040):312-6

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the ~300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.
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http://dx.doi.org/10.1126/science.1205805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310437PMC
July 2011