Biology subjects

Sekhar, A.

Publications and source records attributed to Sekhar, A..

2 recordsLinked to original sources

bioRxiv2025

Morpheus: A fragment-based algorithm to predict metamorphic behaviour in proteins across proteomes

Functionally important "fold-switching" proteins, which do not obey the classical folding dogma, are now thought to be widespread. Algorithms that can accurately annotate fold-switching proteins from sequence information can help uncover the true extent of the "metamorphome". Here, we present Morpheus, a fragment-based classification approach, that works by analysing the diversity of structures within a query protein sequence. Morpheus exhaustively curates and uses fragment structural data from the protein data bank as well as the AlphaFold Protein Structure Database. We employed our algorithm on 57 different proteomes consisting of a total of 601,218 proteins and identified about 10% of these proteins with the ability to fold switch. Additionally, we provide a web server for Morpheus to test for metamorphic propensities for user-defined sequences (http://mbu.iisc.ac.in/[~]anand/morpheus). Besides screening for metamorphic behaviour in proteomes, our work will be useful in de novo design and engineering of such proteins through further experimentation.

bioinformatics↗

bioRxiv2022

Functional regulation of an intrinsically disordered protein via a conformationally excited state

A longstanding goal in the field of intrinsically disordered proteins (IDP) is to characterize their structural heterogeneity and pinpoint the role of this heterogeneity in IDP function. Here, we use multinuclear chemical exchange saturation (CEST) NMR to determine the structure of a thermally accessible globally folded excited state in equilibrium with the intrinsically disordered native ensemble of a bacterial transcriptional regulator CytR. We further provide evidence from double resonance CEST experiments that the excited state, which structurally resembles the DNA-bound form of CytR, recognizes DNA by means of a folding-before-binding conformational selection pathway. The disorder-to-order regulatory switch in DNA recognition by natively disordered CytR therefore operates through a dynamical variant of the lock-and-key mechanism where the structurally complementary conformation is transiently accessed via thermal fluctuations. One-Sentence SummaryThe intrinsically disordered cytidine repressor binds DNA via a folding-before-binding conformational selection mechanism

biophysics↗