Probing the structural dynamics of the Plasmodium falciparum tunneling-fold enzyme 6-pyruvoyl tetrahydropterin synthase to reveal allosteric drug targeting sites:
- Khairallah, Afrah, Ross, Caroline J, Tastan Bishop, Özlem
- Authors: Khairallah, Afrah , Ross, Caroline J , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163057 , vital:41008 , https://doi.org/10.3389/fmolb.2020.575196
- Description: The de novo folate synthesis pathway is a well-established drug target in the treatment of many infectious diseases. Antimalarial antifolate drugs have proven to be effective against malaria, however, rapid drug resistance has emerged on the two primary targeted enzymes: dihydrofolate reductase and dihydroptoreate synthase. The need to identify alternative antifolate drugs and novel metabolic targets is of imminent importance. The 6-pyruvol tetrahydropterin synthase (PTPS) enzyme belongs to the tunneling fold protein superfamily which is characterized by a distinct central tunnel/cavity. The enzyme catalyzes the second reaction step of the parasite’s de novo folate synthesis pathway and is responsible for the conversion of 7,8-dihydroneopterin to 6-pyruvoyl-tetrahydropterin. In this study, we examine the structural dynamics of Plasmodium falciparum PTPS using the anisotropic network model, to elucidate the collective motions that drive the function of the enzyme and identify potential sites for allosteric modulation of its binding properties.
- Full Text:
- Date Issued: 2020
- Authors: Khairallah, Afrah , Ross, Caroline J , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163057 , vital:41008 , https://doi.org/10.3389/fmolb.2020.575196
- Description: The de novo folate synthesis pathway is a well-established drug target in the treatment of many infectious diseases. Antimalarial antifolate drugs have proven to be effective against malaria, however, rapid drug resistance has emerged on the two primary targeted enzymes: dihydrofolate reductase and dihydroptoreate synthase. The need to identify alternative antifolate drugs and novel metabolic targets is of imminent importance. The 6-pyruvol tetrahydropterin synthase (PTPS) enzyme belongs to the tunneling fold protein superfamily which is characterized by a distinct central tunnel/cavity. The enzyme catalyzes the second reaction step of the parasite’s de novo folate synthesis pathway and is responsible for the conversion of 7,8-dihydroneopterin to 6-pyruvoyl-tetrahydropterin. In this study, we examine the structural dynamics of Plasmodium falciparum PTPS using the anisotropic network model, to elucidate the collective motions that drive the function of the enzyme and identify potential sites for allosteric modulation of its binding properties.
- Full Text:
- Date Issued: 2020
The In Silico Prediction of hotspot residues that contribute to the structural stability of subunit interfaces of a Picornavirus Capsid:
- Upfold, Nicole, Ross, Caroline J, Tastan Bishop, Özlem, Knox, Caroline M
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Knox, Caroline M
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149970 , vital:38919 , https://doi.org/10.3390/v12040387
- Description: The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler’s murine encephalomyelitis virus (TMEV) capsid.
- Full Text:
- Date Issued: 2020
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Knox, Caroline M
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149970 , vital:38919 , https://doi.org/10.3390/v12040387
- Description: The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler’s murine encephalomyelitis virus (TMEV) capsid.
- Full Text:
- Date Issued: 2020
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