Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.24.27 (
thermolysin
)
1,894
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Germline mutations in
NUDT15
cause thiopurine intolerance during treatment of leukemia or autoimmune diseases. Previously, it has been shown that the mutations affect the enzymatic activity of the
NUDT15
hydrolase due to decreased protein stability in vivo. Here we provide structural insights into protein destabilization in R139C and V18I mutants using
thermolysin
-based proteolysis and H/D exchange followed by mass spectrometry. Both mutants exhibited destabilization of the catalytic site, which was more pronounced at higher temperature. This structural perturbation is shared by the mutations despite their different positions within the protein structure. Reaction products of
NUDT15
reverted these conformational abnormalities, demonstrating the importance of ligands for stabilization of a native state of the mutants. This study shows the action of pharmacogenetic variants in
NUDT15
in a context of protein structure, which might open novel directions in personalized chemotherapy.
...
PMID:Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site. 3063 26
