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Ruth  Nussinov, Ph.D.

Ruth Nussinov, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
Cancer Innovation Laboratory

RESEARCH SUMMARY

Dr. Nussinov is a biologist by training. In 1999 she proposed that all conformations preexist and that the changes in their distributions to maintain their chemical equilibrium, following mutations and binding, is the origin of allostery. She also proposed that the associated conformational and dynamic changes propagate in the structures through favored pathways, and that this is how allostery impacts function. Her biological outlook viewed the monumental free energy landscape concept in terms of function, leading to her landmark postulate that all functional conformations already exist, and that function makes use of them, and can be explained in these terms. She further proposed that the ability to perform a biological function is determined by how stable, or populated, a macromolecule is in its active, ON conformation. In 1999 she already also postulated that in both allosteric and non-allosteric binding, the deceptively rigid snapshot images of protein motion observed by crystallography can be explained by the presence of low barriers around the bottom of the funnel and shifts toward chemical equilibrium in favor of the functional bound states. She pioneered the “conformational selection and population shift” (1999) as an alternative to the “induced fit” text-book model to explain the molecular mechanism of recognition and postulated that the population shift, that is a redistribution of the ensemble, underlies allosteric regulation. In line with this, she posited that activation by oncogenic mutations mimic the activation mechanism of the wild-type protein. Experimental data over two decades supported these fundamental concepts, and as evidenced in the literature, by now a vast number of experimental and computational studies take them as established facts. Nussinov further applied these concepts to unravel the structural mechanisms of allosteric drug action and to formulate determinants of agonist/antagonist drug design. Her group unraveled the detailed oncogenic activation of PI3K, B-Raf, and PTEN and the structural basis for oncogenic Ras signaling at the membrane, also confirmed by experiments. Her pioneering work has contributed to extraordinary advances in understanding the conformational behaviors of biological macromolecules, and their uncontrolled actions in disease.

Dr. Nussinov served as the Editor-in-Chief of PLOS Computational Biology and is currently Editor-in-Chief of Current Opinion in Structural Biology.  She is an elected Fellow of the Biophysical Society, the International Society of Computational Biology (ISCB), the American Physical Society (APS), and the American Institute for Medical and Biological Engineering (AIMBE).  She was recognized by multiple Domestic and International Awards. She has been designated multiple times a Highly Cited Researcher (ranking among the top 3000 researchers or 1% across all fields according to Thomson Reuters Essential Science Indicators, http://highlycited.com/ "earning them the mark of exceptional impact"). and her impact among the top female scientists was ranked as 44 in the US (66 world-wide), https://research.com/scientists-rankings/best-female-scientists. Most of her publications are conceptualized and driven by her group.

A personal scientific overview of her biography has been published in

 http://www.sciencedirect.com/science/article/pii/S0165614717301293?via%3Dihub Trends Pharmacol Sci. 2017 Sep;38(9):761-763. doi: 10.1016/j.tips.2017.06.008.

Autobiography of Ruth Nussinov.
Nussinov R. J Phys Chem B. 2021 Jul 1;125(25):6735-6739. doi:10.1021/acs.jpcb.1c04719

Areas of Expertise

1) protein structure, dynamics and function 2) signaling 3) allosteric drugs 4) cellular networks 5) oncogenic proteins 6) computational biology

Publications

Selected Recent Publications

The mechanism of activation of MEK1 by B-Raf and KSR1

Maloney RC, Zhang M, Liu Y, Jang H, Nussinov R.
Cell Mol. Life Sci.. 79/5: 281, doi: 10.1007/s00018-022-04296-0 , 2022.
Full-Text Article
[ Journal Article ]

A new view of activating mutations in cancer

Nussinov R, Tsai CJ, Jang H.
Cancer Res.. Sep 7: doi: 10.1158/0008-5472.CAN-22-2125., 2022.
Full-Text Article
[ Journal Article ]

How can same-gene mutations promote both cancer and developmental disorders?

Nussinov R, Tsai CJ, Jang H.
Sci. Adv. . 8/2: eabm2059, doi: 10.1126/sciadv.abm2059., 2022.
Full-Text Article
[ Journal Article ]

AlphaFold, Artificial Intelligence (AI), and Allostery

Nussinov R, Zhang M, Liu Y, Jang H
J. Phys. Chem. B. 126/34: 6372-6383, doi: 10.1021/acs.jpcb.2c04346., 2022.
Full-Text Article
[ Journal Article ]

Neurodevelopmental disorders, immunity, and cancer are connected

Nussinov R, Tsai CJ, Jang H.
iScience. 25/6: 104492, doi: 10.1016/j.isci.2022.104492. , 2022.
Full-Text Article
[ Journal Article ]

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Team

Senior Computational Scientist (Contr.)
Hyunbum Jang, Ph.D.
Predoctoral Visiting Fellow (Graduate Student)
Tsung-Jen Liao
Postdoctoral Fellow (Visiting) (Contr.)
Hansaim Lim, Ph.D.
Postdoctoral Fellow (CRTA)
Ryan Maloney, Ph.D.
Guest Researcher (Contr.)
Emine Ozdemir
Guest Researcher (Contr.)
Amarda Shehu, Ph.D.
Programmer/Analyst IV (Contr.)
Chung-Jung Tsai, Ph.D.
Computational Scientist (Contr.)
Mingzhen Zhang, Ph.D.