Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F16%3A00465607" target="_blank" >RIV/61388963:_____/16:00465607 - isvavai.cz</a>
Alternative codes found
RIV/60077344:_____/16:00465607
Result on the web
<a href="http://www.nature.com/articles/srep35894" target="_blank" >http://www.nature.com/articles/srep35894</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/srep35894" target="_blank" >10.1038/srep35894</a>
Alternative languages
Result language
angličtina
Original language name
Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase
Original language description
Human African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, Trypanosoma brucei (Tbr). Due to the debilitating side effects of the current therapeutics and the emergence of resistance to these drugs, new medications for this disease need to be developed. One potential new drug target is 6-oxopurine phosphoribosyltransferase (PRT), an enzyme central to the purine salvage pathway and whose activity is critical for the production of the nucleotides (GMP and IMP) required for DNA/RNA synthesis within this protozoan parasite. Here, the first crystal structures of this enzyme have been determined, these in complex with GMP and IMP and with three acyclic nucleoside phosphonate (ANP) inhibitors. The K-i values for GMP and IMP are 30.5 mu M and 77 mu M, respectively. Two of the ANPs have K-i values considerably lower than for the nucleotides, 2.3 mu M (with guanine as base) and 15.8 mu M (with hypoxanthine as base). The crystal structures show that when two of the ANPs bind, they induce an unusual conformation change to the loop where the reaction product, pyrophosphate, is expected to bind. This and other structural differences between the Tbr and human enzymes suggest selective inhibitors for the Tbr enzyme can be designed.
Czech name
—
Czech description
—
Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
CC - Organic chemistry
OECD FORD branch
—
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2016
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Scientific Reports
ISSN
2045-2322
e-ISSN
—
Volume of the periodical
6
Issue of the periodical within the volume
Oct 27
Country of publishing house
GB - UNITED KINGDOM
Number of pages
14
Pages from-to
—
UT code for WoS article
000386762800001
EID of the result in the Scopus database
2-s2.0-84992671908