Allosteric inhibition explained through conformational ensembles sampling distinct “mixed” states

Abstract

Graphical abstract

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

“…In the last decades, the long-term impetus has promoted innovative attempts to tackle the elusive enigma with multidisciplinary approaches. With accumulating evidence of the multiple advantages boosted by allosteric modulation, it has attracted an ever-growing interest in pharmaceutics, and consequently, the combination of orthosteric and allosteric agents is emerging as a revolutionary strategy to overcome resistance, as exemplified by the growing number of successful cases [ 74 , 75 , 76 , 77 , 78 , 79 ]. Accordingly, a series of orthosteric-allosteric drug combinations have proceeded into clinical trials, mostly involving oncology, viruses, and autoimmune disorders [ 17 ].…”

Atomic-scale insights into allosteric inhibition and evolutional rescue mechanism of Streptococcus thermophilus Cas9 by the anti-CRISPR protein AcrIIA6

“…have attempted to exploit this natural CRISPR-Cas regulator repertoire [18] , [56] , [57] , [58] ; moreover, computational-guided engineering of existing Acr-based structural information has been recognised as a promising approach for expanding Acr inhibition [93] . Currently, the broad spectrum of Cas endonucleases regulated by Acrs compensates for the current scarcity of regulation strategies for Cas endonucleases with different sizes, fidelity, and PAM promiscuity from that of the established CRISPR-SpCas9-based toolkit [4] , [7] , [45] , [46] , [94] , which would enable controllable and customised CRISPR-based techniques for different purposes (i.e. manipulation of differently sized genes).…”

Joint neutron/molecular dynamics vibrational spectroscopy reveals softening of HIV-1 protease upon binding of a tight inhibitor

“…The dynamical nature of biomacromolecules is essential for their biological activities such as cellular association, self-assembly and enzyme catalysis and to further reproductive fitness and self-organization. [1][2][3][4][5] The dynamic behavior of biomacromolecules spans at least fifteen orders of magnitude in time, occurring at timescales ranging from femtoseconds (fs or 10 À15 s) to seconds in pursuit of environmental interactions to support life. 6 In protein molecules, atomic bond stretching and bending are among the fastest motions clocking in at 1-10 2 fs.…”