TY - JOUR
T1 - Advanced Methods for Accessing Protein Shape-Shifting Present New Therapeutic Opportunities
AU - Knoverek, Catherine R.
AU - Amarasinghe, Gaya K.
AU - Bowman, Gregory R.
N1 - Funding Information:
This work was funded by NSF CAREER Award MCB-1552471 and NIH grants R01 GM12400701 , U19 AI109664-04 , U19 AI109945-03 , and P01 AI120943-01A1 . G.R.B. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and a Packard Fellowship for Science and Engineering from The David & Lucile Packard Foundation. C.R.K holds a MilliporeSigma Fellowship. We are grateful to Daisy W. Leung for helpful comments.
Funding Information:
This work was funded by NSF CAREER Award MCB-1552471 and NIH grants R01 GM12400701, U19 AI109664-04, U19 AI109945-03, and P01 AI120943-01A1. G.R.B. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and a Packard Fellowship for Science and Engineering from The David & Lucile Packard Foundation. C.R.K holds a MilliporeSigma Fellowship. We are grateful to Daisy W. Leung for helpful comments.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2019/4
Y1 - 2019/4
N2 - A protein is a dynamic shape-shifter whose function is determined by the set of structures it adopts. Unfortunately, atomically detailed structures are only available for a few conformations of any given protein, and these structures have limited explanatory and predictive power. Here, we provide a brief historical perspective on protein dynamics and introduce recent advances in computational and experimental methods that are providing unprecedented access to protein shape-shifting. Next, we focus on how these tools are revealing the mechanism of allosteric communication and features like cryptic pockets; both of which present new therapeutic opportunities. A major theme is the importance of considering the relative probabilities of different structures and the control one can exert over protein function by modulating this balance.
AB - A protein is a dynamic shape-shifter whose function is determined by the set of structures it adopts. Unfortunately, atomically detailed structures are only available for a few conformations of any given protein, and these structures have limited explanatory and predictive power. Here, we provide a brief historical perspective on protein dynamics and introduce recent advances in computational and experimental methods that are providing unprecedented access to protein shape-shifting. Next, we focus on how these tools are revealing the mechanism of allosteric communication and features like cryptic pockets; both of which present new therapeutic opportunities. A major theme is the importance of considering the relative probabilities of different structures and the control one can exert over protein function by modulating this balance.
KW - allostery
KW - cryptic pockets
KW - protein dynamics
UR - http://www.scopus.com/inward/record.url?scp=85058240921&partnerID=8YFLogxK
U2 - 10.1016/j.tibs.2018.11.007
DO - 10.1016/j.tibs.2018.11.007
M3 - Review article
C2 - 30555007
AN - SCOPUS:85058240921
SN - 0968-0004
VL - 44
SP - 351
EP - 364
JO - Trends in Biochemical Sciences
JF - Trends in Biochemical Sciences
IS - 4
ER -