Structure and dynamics of pteridine reductase 1 : the key phenomena relevant to enzyme function and drug design
© 2023. The Author(s)..
Pteridine reductase 1 (PTR1) is a folate and pterin pathway enzyme unique for pathogenic trypanosomatids. As a validated drug target, PTR1 has been the focus of recent research efforts aimed at finding more effective treatments against human parasitic diseases such as leishmaniasis or sleeping sickness. Previous PTR1-centered structural studies highlighted the enzyme characteristics, such as flexible regions around the active site, highly conserved structural waters, and species-specific differences in pocket properties and dynamics, which likely impacts the binding of natural substrates and inhibitors. Furthermore, several aspects of the PTR1 function, such as the substrate inhibition phenomenon and the level of ligand binding cooperativity in the enzyme homotetramer, likely related to the global enzyme dynamics, are poorly known at the molecular level. We postulate that future drug design efforts could greatly benefit from a better understanding of these phenomena through studying both the local and global PTR1 dynamics. This review highlights the key aspects of the PTR1 structure and dynamics relevant to structure-based drug design that could be effectively investigated by modeling approaches. Particular emphasis is given to the perspective of molecular dynamics, what has been accomplished in this area to date, and how modeling could impact the PTR1-targeted drug design in the future.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:52 |
---|---|
Enthalten in: |
European biophysics journal : EBJ - 52(2023), 6-7 vom: 31. Okt., Seite 521-532 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Panecka-Hofman, Joanna [VerfasserIn] |
---|
Links: |
---|
Themen: |
Drug design |
---|
Anmerkungen: |
Date Completed 01.11.2023 Date Revised 03.11.2023 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1007/s00249-023-01677-6 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM361066538 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM361066538 | ||
003 | DE-627 | ||
005 | 20231226084346.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1007/s00249-023-01677-6 |2 doi | |
028 | 5 | 2 | |a pubmed24n1203.xml |
035 | |a (DE-627)NLM361066538 | ||
035 | |a (NLM)37608196 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Panecka-Hofman, Joanna |e verfasserin |4 aut | |
245 | 1 | 0 | |a Structure and dynamics of pteridine reductase 1 |b the key phenomena relevant to enzyme function and drug design |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 01.11.2023 | ||
500 | |a Date Revised 03.11.2023 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2023. The Author(s). | ||
520 | |a Pteridine reductase 1 (PTR1) is a folate and pterin pathway enzyme unique for pathogenic trypanosomatids. As a validated drug target, PTR1 has been the focus of recent research efforts aimed at finding more effective treatments against human parasitic diseases such as leishmaniasis or sleeping sickness. Previous PTR1-centered structural studies highlighted the enzyme characteristics, such as flexible regions around the active site, highly conserved structural waters, and species-specific differences in pocket properties and dynamics, which likely impacts the binding of natural substrates and inhibitors. Furthermore, several aspects of the PTR1 function, such as the substrate inhibition phenomenon and the level of ligand binding cooperativity in the enzyme homotetramer, likely related to the global enzyme dynamics, are poorly known at the molecular level. We postulate that future drug design efforts could greatly benefit from a better understanding of these phenomena through studying both the local and global PTR1 dynamics. This review highlights the key aspects of the PTR1 structure and dynamics relevant to structure-based drug design that could be effectively investigated by modeling approaches. Particular emphasis is given to the perspective of molecular dynamics, what has been accomplished in this area to date, and how modeling could impact the PTR1-targeted drug design in the future | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Review | |
650 | 4 | |a Drug design | |
650 | 4 | |a Enzyme regulation | |
650 | 4 | |a Molecular dynamics | |
650 | 4 | |a Pteridine reductase 1 | |
650 | 4 | |a Substrate inhibition | |
650 | 7 | |a pteridine reductase |2 NLM | |
650 | 7 | |a EC 1.1.1.33 |2 NLM | |
650 | 7 | |a Oxidoreductases |2 NLM | |
650 | 7 | |a EC 1.- |2 NLM | |
650 | 7 | |a Enzyme Inhibitors |2 NLM | |
700 | 1 | |a Poehner, Ina |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t European biophysics journal : EBJ |d 1991 |g 52(2023), 6-7 vom: 31. Okt., Seite 521-532 |w (DE-627)NLM012633011 |x 1432-1017 |7 nnns |
773 | 1 | 8 | |g volume:52 |g year:2023 |g number:6-7 |g day:31 |g month:10 |g pages:521-532 |
856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00249-023-01677-6 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 52 |j 2023 |e 6-7 |b 31 |c 10 |h 521-532 |