Analysis of apo and citraconate-bound hACOD1 (hIRG1) by X-ray crystallography and NMR spectroscopy: structural insights for developing chemotherapeutic agents
Monteiro, D. C. F.; Runge, B.; Fucci, I. J.
Show abstract
In this work, we present the high-resolution structure of human aconitate decarboxylase 1 (hACOD1) in its true apo form (active site empty) as well in complex with the inhibitor citraconate. These two new structures show the architecture of the active site and the structure-activity relationships of citraconate inhibition. Careful analysis of the structures indicates probable dynamics required for substrate/inhibitor binding and catalysis. These observations were further explored using molecular dynamic simulations, which show a clear open-close mechanism of hACOD1 between the A1 and A2 loops, the lid- and helical-domain respectively. As part of the biochemical characterization of the protein, we also developed an alternative kinetic assay which measures the rate of catalysis of hACOD1 by direct observation of the conversion of cis-aconitate to itaconate by NMR spectroscopy. The work herein offers a foundation for structure- and dynamic-driven design of novel hACOD1 inhibitors as novel chemotherapeutics.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Integrative x-ray structure and molecular modeling for the rationalization of procaspase-8 inhibitor potency and selectivity 95%
- Expanding the substrate selectivity of the fimsbactin biosynthetic adenylation domain, FbsH 95%
- Discovery of inhibitors for bacterial Arr enzymes ADP-ribosylating and inactivating rifamycin antibiotics 94%
Similar papers in this journal
- Structural characterization of functionally important chloride binding sites in the marine Vibrio alkaline phosphatase 96%
- Understanding ATP binding to DosS catalytic domain with a short ATP-lid 95%
- Structure and Mechanism of Avermitilol Synthase, a Sesquiterpene Cyclase that Generates a Highly Strained 6-6-3 Tricyclic Alcohol 95%
Similar papers in this journal
- Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors 95%
- Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease 95%
- Conformational plasticity across phylogenetic clusters of RND multidrug efflux pumps and its impact on substrate specificity 95%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.