Cyclin-dependent kinases （CDKs） are critical to the cell cycle and many other biological processes, and as such, are considered as one of the promising targets for therapy against cancer and other diseases. Most pan...Cyclin-dependent kinases （CDKs） are critical to the cell cycle and many other biological processes, and as such, are considered as one of the promising targets for therapy against cancer and other diseases. Most pan-CDK inhibitors bind to the highly conserved catalytic ATP-binding pocket and therefore lack the specificity to prevent side effects. It is desirable to develop drugs targeting non-catalytic pockets for specificity towards individual CDKs. Here we performed a systematic analysis of non-catalytic pockets on CDKs and identified a region underneath the T-loop, which we term TL pocket, for potential inhibitor development. Specifically, we compared the TL pockets of human CDK2 and CDK7-homolog Pfmrk of Plasmodium falciparum, a malaria-causing parasite. Molecular dynamics simulations of several short peptides revealed that this less conserved TL pocket could be used to design potentially specific inhibitors against malaria disease.展开更多
Based on the coherent feedforward transcription regulation loops in somatic cell reprogramming process, a stochastic kinetic model is proposed to study the intrinsic fluctuations in the somatic cell reprogramming. The...Based on the coherent feedforward transcription regulation loops in somatic cell reprogramming process, a stochastic kinetic model is proposed to study the intrinsic fluctuations in the somatic cell reprogramming. The Fano factor formulas of key genes expression level in the coherent feedforward transcription regulation loops are derived by using of Langevin theory. It is found that the internal fluctuations of gene expression levels mainly depend on itself activation ratio and degradation ratio. When the self-activation ratio(or self-degradation ratio) is increased, the Fano factor increases reaches a maximum and then decreases. The susceptibility is used to measure the sensitivity of steady-state response to the variation in systemic parameters. It is found that with the increase of the self-activation ratio(or self-degradation ratio), the susceptibility of steady-state increases at first, it reaches a maximum, and it then decreases. The magnitude of the maximum is increased with the increase of activated ratio by the upstream transcription factor.展开更多
The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate...The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.展开更多
Plants and animals recognize microbial invaders by detecting pathogen-associated molecular patterns (PAMPs) through pattern-recognition receptors (PRRs). This recognition plays a crucial role in plant immunity. The ne...Plants and animals recognize microbial invaders by detecting pathogen-associated molecular patterns (PAMPs) through pattern-recognition receptors (PRRs). This recognition plays a crucial role in plant immunity. The newly discovered protein in plants that responds to bacterial flagellin, i.e., flagellin-sensitive 2 (FLS2), is ubiquitously expressed and present in many plants. The association of FLS2 and BAK1, facilitated by a highly conserved epitope flg22 of flagellin, triggers such downstream immune responses as activated MAPK pathway and elevated reactive oxygen species (ROS) for bacterial defense and plant immunity. Here we study the intrinsic dynamics and conformational change of FLS2 upon the formation of the FLS2–flg22–BAK1 complex. The top intrinsic normal modes and principal structural fluctuation components are very similar, showing two bending modes and one twisting mode. The twisting mode alone, however, accounts for most of the conformational change of FLS2 induced by binding with flg22 and BAK1. This study indicates that flg22 binding suppresses FLS2 conformational fluctuation, especially on the twisting motion, thus facilitating FLS2–BAK1 interaction. A detailed analysis of this sensing mechanism may aid better design on both PRR and peptide mimetics for plant immunity.展开更多
基金Project supported by the National Natural Science Foundation of China(Grant No.11704140)the Natural Science Foundation of Hubei Province,China(Grant No.2017CFB116)+1 种基金the Thousand Talents Plan(Grant No.31103201603)the Self-determined Research Funds of CCNU from the Colleges’Basic Research and Operation of MOE 20205170045 to YZ
文摘Cyclin-dependent kinases （CDKs） are critical to the cell cycle and many other biological processes, and as such, are considered as one of the promising targets for therapy against cancer and other diseases. Most pan-CDK inhibitors bind to the highly conserved catalytic ATP-binding pocket and therefore lack the specificity to prevent side effects. It is desirable to develop drugs targeting non-catalytic pockets for specificity towards individual CDKs. Here we performed a systematic analysis of non-catalytic pockets on CDKs and identified a region underneath the T-loop, which we term TL pocket, for potential inhibitor development. Specifically, we compared the TL pockets of human CDK2 and CDK7-homolog Pfmrk of Plasmodium falciparum, a malaria-causing parasite. Molecular dynamics simulations of several short peptides revealed that this less conserved TL pocket could be used to design potentially specific inhibitors against malaria disease.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11775091 and 11474117)
文摘Based on the coherent feedforward transcription regulation loops in somatic cell reprogramming process, a stochastic kinetic model is proposed to study the intrinsic fluctuations in the somatic cell reprogramming. The Fano factor formulas of key genes expression level in the coherent feedforward transcription regulation loops are derived by using of Langevin theory. It is found that the internal fluctuations of gene expression levels mainly depend on itself activation ratio and degradation ratio. When the self-activation ratio(or self-degradation ratio) is increased, the Fano factor increases reaches a maximum and then decreases. The susceptibility is used to measure the sensitivity of steady-state response to the variation in systemic parameters. It is found that with the increase of the self-activation ratio(or self-degradation ratio), the susceptibility of steady-state increases at first, it reaches a maximum, and it then decreases. The magnitude of the maximum is increased with the increase of activated ratio by the upstream transcription factor.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11904036 and 12175081)Fundamental Research Funds for the Central Universities(Grant No.CCNU22QNOO4)。
文摘The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.
基金Project supported by the National Natural Science Foundation of China (Grant No. 11704140)self-determined research funds of CCNU from the Colleges' Basic Research and Operation of MOE (Grant No. CCNU20TS004) (Y. Z.)the China Scholarship Council Fund (Grant No. 201708420039) (L. P.).
文摘Plants and animals recognize microbial invaders by detecting pathogen-associated molecular patterns (PAMPs) through pattern-recognition receptors (PRRs). This recognition plays a crucial role in plant immunity. The newly discovered protein in plants that responds to bacterial flagellin, i.e., flagellin-sensitive 2 (FLS2), is ubiquitously expressed and present in many plants. The association of FLS2 and BAK1, facilitated by a highly conserved epitope flg22 of flagellin, triggers such downstream immune responses as activated MAPK pathway and elevated reactive oxygen species (ROS) for bacterial defense and plant immunity. Here we study the intrinsic dynamics and conformational change of FLS2 upon the formation of the FLS2–flg22–BAK1 complex. The top intrinsic normal modes and principal structural fluctuation components are very similar, showing two bending modes and one twisting mode. The twisting mode alone, however, accounts for most of the conformational change of FLS2 induced by binding with flg22 and BAK1. This study indicates that flg22 binding suppresses FLS2 conformational fluctuation, especially on the twisting motion, thus facilitating FLS2–BAK1 interaction. A detailed analysis of this sensing mechanism may aid better design on both PRR and peptide mimetics for plant immunity.
