Molecular Mechanism of Selective Substrate Engagement and Inhibitor Dis-engagement of Cysteine Synthase
IR@IMTECH: CSIR-Institute of Microbial Technology, Chandigarh
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| Title |
Molecular Mechanism of Selective Substrate Engagement and Inhibitor Dis-engagement of Cysteine Synthase
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| Creator |
Kaushik, Abhishek
Rahisuddin, R. Saini, Neha Singh, Ravi P. Kaur, Rajveer Kaul, Sukirte Kumaran, Sangaralingam |
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| Subject |
QR Microbiology
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| 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 4-6 log-folds stronger affinity for its natural inhibitor, serine acetyltransferase (SAT), as compared to 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 [1]. 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 analysed structural and substrate-binding features of wild type CS and its ~13 mutants. Results show that CS uses a non-catalytic residue, M120, located 20 Å away from the reaction centre, to discriminate in favour of substrate. M120A and background mutants display significantly reduced substrate binding, catalytic efficiency, and inhibitor binding. Results shows that M120 favours the substrate binding by selectively enhancing the affinity for the substrate and dis-engaging the inhibitor by 20-286 and 5-3 folds respectively. Together, M120 confers a net discriminative force in favour of substrate by 100-858 folds.
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| Publisher |
ASBMB
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| Date |
2020-11-08
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| Type |
Article
PeerReviewed |
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| Relation |
https://www.jbc.org/content/early/2020/11/08/jbc.RA120.014490
http://crdd.osdd.net/open/2617/ |
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| Identifier |
Kaushik, Abhishek and Rahisuddin, R. and Saini, Neha and Singh, Ravi P. and Kaur, Rajveer and Kaul, Sukirte and Kumaran, Sangaralingam (2020) Molecular Mechanism of Selective Substrate Engagement and Inhibitor Dis-engagement of Cysteine Synthase. Journal of Biological Chemistry. ISSN 00219258 (In Press)
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