Nikola P. Pavletich
Solved the crystal structure of the mTOR kinase, revealing the FRB domain as a gatekeeper of its active site, and later showed how RHEB switches mTORC1 on and PRAS40 blocks it
Stephen and Barbara Friedman Chair, Sloan Kettering Institute · Chair, Structural Biology Program, Memorial Sloan Kettering Cancer Center · faculty, Memorial Sloan Kettering Cancer Center (since 1993) · HHMI Investigator (1997–2022) · postdoc, MIT (Carl Pabo lab) · PhD, Johns Hopkins University School of Medicine (1991) · BS in Chemistry, Caltech (1988)
Pavletich Lab, Memorial Sloan Kettering Cancer Center (New York, New York, USA) ↗ Lab lineagetrained under Carl O. Pabo →
Portrait: Memorial Sloan Kettering Cancer Center
In 2013, Pavletich's lab solved the first crystal structure of the mTOR kinase domain itself — a feat that had eluded structural biologists for years because mTOR is a huge, flexible, membrane-associated enzyme. The structure showed why mTOR's active site is so hard for drugs and substrates to reach: it sits in a deep recess, and the FRB domain acts as a lid or 'gatekeeper' controlling access, explaining at the atomic level exactly how the FKBP12–rapamycin complex jams the site shut, and why activating cancer mutations cluster around it. In 2017, his group followed up with structures of the full mTORC1 complex bound to its regulators, showing mechanistically how the small GTPase RHEB docks onto mTOR and allosterically realigns its catalytic residues to turn the kinase on, while the inhibitory subunit PRAS40 works by occluding the substrate-binding surface.
The mTOR work came after two decades in which Pavletich's lab built a track record of solving landmark, previously 'unsolvable' cancer-related protein structures by X-ray crystallography: the p53 tumour-suppressor core domain bound to DNA (1994); the MDM2–p53 transactivation-domain complex, which defined the druggable pocket later exploited by MDM2-inhibitor cancer drugs such as the Nutlins (1996); the p27Kip1–cyclin A–Cdk2 complex, showing how p27 both rearranges and physically plugs the kinase's ATP cleft to halt the cell cycle (1996); and the VHL–ElonginC–ElonginB complex, revealing the tumorigenic hot-spot on the von Hippel–Lindau protein (1999).
Pavletich trained in chemistry at Caltech, earned his PhD at Johns Hopkins, and did postdoctoral work with Carl Pabo at MIT before joining Memorial Sloan Kettering Cancer Center's faculty in 1993, becoming an HHMI Investigator in 1997 and Chair of the Structural Biology Program in 2003. He was elected to the National Academy of Sciences in 2012. His lab's current focus has extended from mTOR to the structural biology of DNA-damage-response machinery, including the ATR and ATM checkpoint kinases and the Fanconi anemia pathway.
Milestones in the Atlas
A selection, not a full bibliography: only papers that meet the Atlas inclusion criteria.
| Year | Evidence | Study |
|---|---|---|
| 2013 | M | mTOR kinase structure, mechanism and regulation YAN2013 Solves the crystal structure of the mTOR kinase domain, showing how its FRB domain gates a deeply buried active site and how FKBP12-rapamycin blocks it. |
| 2017 | M | Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40 YAN2017 Determines structures of mTORC1 bound to its regulators, showing how RHEB allosterically activates the kinase while PRAS40 holds it inhibited. |
Co-authors in the Atlas 2
People with a profile here who share at least one study with Nikola P. Pavletich.
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- Haijuan Yang 2 shared studies Solved, as first author in the Pavletich lab, the crystal structure of the mTOR kinase and the structure of mTORC1 activated by RHEB
- Hyo J Yang 2 shared studies Researcher in Nikola Pavletich's structural biology laboratory at Memorial Sloan Kettering and co-author of the two Nature papers that showed the atomic structure of mTOR and of mTORC1
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