ArticleThe Journal of biological chemistry2016
An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 28 citations in OpenAlex.
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- Attacking COVID-19 Progression Using Multi-Drug Therapy for Synergetic Target Engagement.Biomolecules · 2021Article
- A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor.Biomolecules · 2020Article
- The bacterial metalloprotease NleD selectively cleaves mitogen-activated protein kinases that have high flexibility in their activation loop.The Journal of biological chemistry · 2020Article
- Molecular Dynamics Simulations Suggest a Non-Doublet Decoding Model of -1 Frameshifting by tRNABiomolecules · 2019Article
- Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.Nature reviews. Neurology · 2019Review
- Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin.The Journal of biological chemistry · 2019Article
- Conformational entropy of a single peptide controlled under force governs protease recognition and catalysis.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Protein modeling and clinical description of a novel in-frame GLB1 deletion causing GM1 gangliosidosis type II.Molecular genetics & genomic medicine · 2018Article
- Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases.The Biochemical journal · 2018Article
- Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy.Oncotarget · 2018Article
- Article
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
The molecular basis of enzyme catalytic power and specificity derives from dynamic interactions between enzyme and substrate during catalysis. Although considerable effort has been devoted to understanding how conformational dynamics within enzymes affect catalysis, the role of conformational dynamics within protein substrates has not been addressed. Here, we examine the importance of substrate dynamics in the cleavage of Kunitz-bovine pancreatic trypsin inhibitor protease inhibitors by mesotrypsin, finding that the varied conformational dynamics of structurally similar substrates can profoundly impact the rate of catalysis. A 1.4-Å crystal structure of a mesotrypsin-product complex formed with a rapidly cleaved substrate reveals a dramatic conformational change in the substrate upon proteolysis. By using long all-atom molecular dynamics simulations of acyl-enzyme intermediates with proteolysis rates spanning 3 orders of magnitude, we identify global and local dynamic features of substrates on the nanosecond-microsecond time scale that correlate with enzymatic rates and explain differential susceptibility to proteolysis. By integrating multiple enhanced sampling methods for molecular dynamics, we model a viable conformational pathway between substrate-like and product-like states, linking substrate dynamics on the nanosecond-microsecond time scale with large collective substrate motions on the much slower time scale of catalysis. Our findings implicate substrate flexibility as a critical determinant of catalysis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.