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Molecular mechanism of selective substrate engagement and inhibitor disengagement of cysteine synthase

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Molecular mechanism of selective substrate engagement and inhibitor disengagement of cysteine synthase
 
Creator Kaushik, Abhishek
Rahisuddin, R.
Saini, Neha
Singh, Ravi P.
Kaur, Rajveer
Koul, Sukirte
Kumaran, S.
 
Subject QR Microbiology
 
Description O-acetyl serine sulfhydrylase (OASS), referred to as cysteine synthase (CS), synthesizes cysteine from O-acetyl serine (OAS) and sulfur in bacteria and plants. The inherent challenge for CS is to overcome 4 to 6 log-folds stronger affinity for its natural inhibitor, serine acetyltransferase (SAT), as compared with its affinity for substrate, OAS. Our recent study showed that CS employs a novel competitive-allosteric mechanism to selectively recruit its substrate in the presence of natural inhibitor. In this study, we trace the molecular features that control selective substrate recruitment. To generalize our findings, we used CS from three different bacteria (Haemophilus, Salmonella, and Mycobacterium) as our model systems and analyzed structural and substrate-binding features of wild-type CS and its ∼13 mutants. Results show that CS uses a noncatalytic residue, M120, located 20 Å away from the reaction center, to discriminate in favor of substrate. M120A and background mutants display significantly reduced substrate binding, catalytic efficiency, and inhibitor binding. Results shows that M120 favors the substrate binding by selectively enhancing the affinity for the substrate and disengaging the inhibitor by 20 to 286 and 5- to 3-folds, respectively. Together, M120 confers a net discriminative force in favor of substrate by 100- to 858-folds.
 
Publisher National Library of Medicine
 
Date 2021-06
 
Type Article
PeerReviewed
 
Identifier Kaushik, Abhishek and Rahisuddin, R. and Saini, Neha and Singh, Ravi P. and Kaur, Rajveer and Koul, Sukirte and Kumaran, S. (2021) Molecular mechanism of selective substrate engagement and inhibitor disengagement of cysteine synthase. JOURNAL OF BIOLOGICAL CHEMISTRY, 296.
 
Relation http://crdd.osdd.net/open/2711/