Computational perspective and evaluation of plausible catalytic mechanisms of peptidyl-prolyl cis–trans isomerases

Ladani, Safieh Tork; Souffrant, Michael; Barman, Arghya; Hamelberg, Donald

doi:10.1016/j.bbagen.2014.12.023

Cited by 14 publications

(17 citation statements)

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“…The catalytic mechanism of PPIases does not involve any bond formation or breakage, but hinges instead on rotation around the peptidyl-prolyl bond, which is at least partially mediated by preferential stabilization of the twisted transition state [ 9 , 10 ]. In the case of the cyclophilins, there has been some debate as to whether it is the part N- or C-terminal to the peptidyl-prolyl bond that rotates [ 36 – 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nature has therefore evolved three families of peptidyl-prolyl isomerases (PPIases) to facilitate cis / trans isomerization: FK506-binding proteins (FKBPs), cyclophilins, and parvulins [ 8 , 9 ]. These enzymes presumably all function by stabilizing the transition state, resulting in an effective rate constant for the catalyzed reaction of up to 10 8 M −1 s −1 [ 9 ], but their mechanisms are not well understood [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular insights into substrate recognition and catalytic mechanism of the chaperone and FKBP peptidyl-prolyl isomerase SlyD

et al. 2016

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BackgroundPeptidyl-prolyl isomerases (PPIases) catalyze cis/trans isomerization of peptidyl-prolyl bonds, which is often rate-limiting for protein folding. SlyD is a two-domain enzyme containing both a PPIase FK506-binding protein (FKBP) domain and an insert-in-flap (IF) chaperone domain. To date, the interactions of these domains with unfolded proteins have remained rather obscure, with structural information on binding to the FKBP domain being limited to complexes involving various inhibitor compounds or a chemically modified tetrapeptide.ResultsWe have characterized the binding of 15-residue-long unmodified peptides to SlyD from Thermus thermophilus (TtSlyD) in terms of binding thermodynamics and enzyme kinetics through the use of isothermal titration calorimetry, nuclear magnetic resonance spectroscopy, and site-directed mutagenesis. We show that the affinities and enzymatic activity of TtSlyD towards these peptides are much higher than for the chemically modified tetrapeptides that are typically used for activity measurements on FKBPs. In addition, we present a series of crystal structures of TtSlyD with the inhibitor FK506 bound to the FKBP domain, and with 15-residue-long peptides bound to either one or both domains, which reveals that substrates bind in a highly adaptable fashion to the IF domain through β-strand augmentation, and can bind to the FKBP domain as both types VIa1 and VIb-like cis-proline β-turns. Our results furthermore provide important clues to the catalytic mechanism and support the notion of inter-domain cross talk.ConclusionsWe found that 15-residue-long unmodified peptides can serve as better substrate mimics for the IF and FKBP domains than chemically modified tetrapeptides. We furthermore show how such peptides are recognized by each of these domains in TtSlyD, and propose a novel general model for the catalytic mechanism of FKBPs that involves C-terminal rotation around the peptidyl-prolyl bond mediated by stabilization of the twisted transition state in the hydrophobic binding site.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0300-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular insights into substrate recognition and catalytic mechanism of the chaperone and FKBP peptidyl-prolyl isomerase SlyD

et al. 2016

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“…In contrast, peptidyl-prolyl cis-trans isomerase (PPIase) and its subunits were up-regulated in V79 cells cultured in the DUGL. PPIase represents a rate limiting step in protein folding, catalyses cis to trans isomerization of peptidyl prolyl bonds [37,38] and is involved in many biological processes. PPIase has been implicated in stress tolerance in wheat; therefore, PPIase activity in V79 cells may have been responsible for enhanced protection against decreased background radiation [37].…”

Section: Discussionmentioning

confidence: 99%

Proteomics provides insights into the inhibition of Chinese hamster V79 cell proliferation in the deep underground environment

Liu

et al. 2020

Preprint

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Background: To characterize the environment of deep underground laboratory (DUGL) with a rock cover of 1470m and observe the effect of the DUGL environment on the growth and metabolism of Chinese hamster V79 cells. Results: Six environmental parameters in the DUGL and an above ground laboratory (AGL; control) were monitored. Compared to the AGL, O2 concentration was not significantly different, total γ ray dose rate was significantly lower (p=0.005), and relative humidity (p<0.001), air pressure (p<0.001), and concentration of CO2 and radon gas (p<0.001) were significantly higher in the DUGL. The growth curves of cultured V79 cells showed cell proliferation was slower in the DUGL. Tandem mass tag (TMT) proteomics analysis was performed to identify differentially abundant proteins (DAPs) in V79 cells cultured in the DUGL and AGL. Parallel Reaction Monitoring (PRM) was conducted to verify TMT results. TMT detected 980 DAPs, defined as proteins with a ≥1.2-absolute fold change in relative abundance (p <0.05) between V79 cells cultured in the DUGL and AGL. Of these, 576 proteins were up-regulated and 404 proteins were down-regulated in V79 cells cultured in the DUGL. GO term enrichment analysis of up-regulated proteins revealed enrichment of proteins involved in translation, ribosome, proton-transporting ATP synthase activity, oxygen binding, and oxygen transporter activity et al. GO term enrichment analysis of downregulated proteins demonstrated enrichment of proteins involved in the endoplasmic reticulum lumenand respiratory chain. KEGG pathway analysis revealed that ribosome (p<0.001), base excision repair (p<0.001), RNA transport (p=0.009), Huntington's disease (p=0.023), and oxidative phosphorylation (OXPPL) (p=0.035) pathways were significantly enriched. Conclusion: Proliferation of V79 cells was inhibited in the DUGL, likely because cells were exposed to reduced cosmic ray muons flux. There were apparent changes in the proteome profile of the V79 cells cultured in the DUGL, which affected proteins related to the ribosome, RNA transport, translation, energy metabolism, and DNA repair.These proteins may have induced cellular changes that delayed proliferation but enhanced survival, making the V79 cells adaptable to the changing environment. Our findings provide insight into the cellular stress response that is triggered in the absence of normal levels of radiation.

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“…45 Cis-trans isomerization is slow and is catalyzed by PPIases through stabilization of the transition state without the formation or the breakage of any covalent bond. 46 Interaction of CypA with Cyclosporine A, an immunosuppressive and antirejection drug that is often given to patients after organ transplants, 47 lowers the T-cell activation and thus the immune response. There is an increasing number of reports that specifically link CypA to various types of cancers 48 mainly due to their over-expression, suggesting a potential prognostic role for CypA.…”

Section: Enhanced Sampling Of Potential Drug Targets With Acceleratedmentioning

confidence: 99%

“…Cyclophilin A (CypA) belongs to the ubiquitous family of peptidyl prolyl cis – trans isomerases (PPIases) that is known to be involved in a host of biochemical processes such as protein folding, regulation of apoptosis, molecular chaperone activity, protection of mitochondria, and eliciting the immune response by binding to the transmembrane protein CD147 . Cis – trans isomerization is slow and is catalyzed by PPIases through stabilization of the transition state without the formation or the breakage of any covalent bond . Interaction of CypA with Cyclosporine A, an immunosuppressive and anti‐rejection drug that is often given to patients after organ transplants, lowers the T‐cell activation and thus the immune response.…”

Section: Introductionmentioning

confidence: 99%

Enhanced molecular dynamics sampling of drug target conformations

Rodriguez-Bussey

Doshi²,

Hamelberg³

2015

Biopolymers

Self Cite

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Computational docking and virtual screening are two main important methods employed in structure-based drug design. Unlike the traditional approach that allows docking of a flexible ligand against a handful of receptor structures, receptor flexibility has now been appreciated and increasingly incorporated in computer-aided docking. Using a diverse set of receptor conformations increases the chances of finding potential drugs and inhibitors. Molecular dynamics (MD) is greatly useful to generate various receptor conformations. However, the diversity of the structures of the receptor, which is usually much larger than the ligand, depends on the sampling efficiency of MD. Enhanced sampling methods based on accelerated molecular dynamics (aMD) can alleviate the sampling limitation of conventional MD and aid in representation of the phase space to a much greater extent. RaMD-db, a variant of aMD that applies boost potential to the rotatable dihedrals and non-bonded diffusive degrees of freedom has been proven to reproduce the equilibrium properties more accurately and efficiently than aMD. Here, we discuss recent advances in the aMD methodology and review the applicability of RaMD-db as an enhanced sampling method. RaMD-db is shown to be able to generate a broad distribution of structures of a drug target, Cyclophilin A. These structures that have never been observed previously in very long conventional MD can be further used for structure-based computer-aided drug discovery, and docking, and thus, in the identification and design of potential novel inhibitors.

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Computational perspective and evaluation of plausible catalytic mechanisms of peptidyl-prolyl cis–trans isomerases

Cited by 14 publications

References 102 publications

Molecular insights into substrate recognition and catalytic mechanism of the chaperone and FKBP peptidyl-prolyl isomerase SlyD

Molecular insights into substrate recognition and catalytic mechanism of the chaperone and FKBP peptidyl-prolyl isomerase SlyD

Proteomics provides insights into the inhibition of Chinese hamster V79 cell proliferation in the deep underground environment

Enhanced molecular dynamics sampling of drug target conformations

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