The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2)

<p>Abstract</p> <p>Background</p> <p>Imatinib represents the first in a class of drugs targeted against chronic myelogenous leukemia to enter the clinic, showing excellent efficacy and specificity for Abl, Kit, and PDGFR kinases. Recent screens carried out to find off-target proteins that bind to imatinib identified the oxidoreductase NQO2, a flavoprotein that is phosphorylated in a chronic myelogenous leukemia cell line.</p> <p>Results</p> <p>We examined the inhibition of NQO2 activity by the Abl kinase inhibitors imatinib, nilotinib, and dasatinib, and obtained IC₅₀values of 80 nM, 380 nM, and >100 μM, respectively. Using electronic absorption spectroscopy, we show that imatinib binding results in a perturbation of the protein environment around the flavin prosthetic group in NQO2. We have determined the crystal structure of the complex of imatinib with human NQO2 at 1.75 Å resolution, which reveals that imatinib binds in the enzyme active site, adjacent to the flavin isoalloxazine ring. We find that phosphorylation of NQO2 has little effect on enzyme activity and is therefore likely to regulate other aspects of NQO2 function.</p> <p>Conclusion</p> <p>The structure of the imatinib-NQO2 complex demonstrates that imatinib inhibits NQO2 activity by competing with substrate for the active site. The overall conformation of imatinib when bound to NQO2 resembles the folded conformation observed in some kinase complexes. Interactions made by imatinib with residues at the rim of the active site provide an explanation for the binding selectivity of NQO2 for imatinib, nilotinib, and dasatinib. These interactions also provide a rationale for the lack of inhibition of the related oxidoreductase NQO1 by these compounds. Taken together, these studies provide insight into the mechanism of NQO2 inhibition by imatinib, with potential implications for drug design and treatment of chronic myelogenous leukemia in patients.</p

The crystal structure of the catalytic domain of a eukaryotic guanylate cyclase

<p>Abstract</p> <p>Background</p> <p>Soluble guanylate cyclases generate cyclic GMP when bound to nitric oxide, thereby linking nitric oxide levels to the control of processes such as vascular homeostasis and neurotransmission. The guanylate cyclase catalytic module, for which no structure has been determined at present, is a class III nucleotide cyclase domain that is also found in mammalian membrane-bound guanylate and adenylate cyclases.</p> <p>Results</p> <p>We have determined the crystal structure of the catalytic domain of a soluble guanylate cyclase from the green algae <it>Chlamydomonas reinhardtii </it>at 2.55 Å resolution, and show that it is a dimeric molecule.</p> <p>Conclusion</p> <p>Comparison of the structure of the guanylate cyclase domain with the known structures of adenylate cyclases confirms the close similarity in architecture between these two enzymes, as expected from their sequence similarity. The comparison also suggests that the crystallized guanylate cyclase is in an inactive conformation, and the structure provides indications as to how activation might occur. We demonstrate that the two active sites in the dimer exhibit positive cooperativity, with a Hill coefficient of ~1.5. Positive cooperativity has also been observed in the homodimeric mammalian membrane-bound guanylate cyclases. The structure described here provides a reliable model for functional analysis of mammalian guanylate cyclases, which are closely related in sequence.</p

Global exposure of population and land‐use to meteorological droughts under different warming levels and SSPs: a CORDEX‐based study

Global warming is likely to cause a progressive drought increase in some regions, but how population and natural resources will be affected is still underexplored. This study focuses on global population, forests, croplands and pastures exposure to meteorological drought hazard in the 21st century, expressed as frequency and severity of drought events. As input, we use a large ensemble of climate simulations from the Coordinated Regional Climate Downscaling Experiment (CORDEX), population projections from the NASA-SEDAC dataset and land-use projections from the Land-Use Harmonization 2 project for 1981–2100. The exposure to drought hazard is presented for five Shared Socioeconomic Pathways (SSP1-SSP5) at four Global Warming Levels (GWLs: 1.5°C to 4°C). Results show that considering only Standardized Precipitation Index (SPI; based on precipitation), the SSP3 at GWL4 projects the largest fraction of the global population (14%) to experience an increase in drought frequency and severity (versus 1981–2010), with this value increasing to 60% if temperature is considered (indirectly included in the Standardized Precipitation-Evapotranspiration Index, SPEI). With SPEI, considering the highest GWL for each SSP, 8 (for SSP2, SSP4, SSP5) and 11 (SSP3) billion people, that is, more than 90%, will be affected by at least one unprecedented drought. For SSP5 at GWL4, approximately 2 × 10$^{6}$ km$^{2}$ of forests and croplands (respectively, 6% and 11%) and 1.5 × 10$^{6}$ km$^{2}$ of pastures (19%) will be exposed to increased drought frequency and severity according to SPI, but for SPEI this extent will rise to 17 × 10$^{6}$ km$^{2}$ of forests (49%), 6 × 10$^{6}$ km$^{2}$ of pastures (78%) and 12 × 10$^{6}$ km$^{2}$ of croplands (67%), being mid-latitudes the most affected. The projected likely increase of drought frequency and severity significantly increases population and land-use exposure to drought, even at low GWLs, thus extensive mitigation and adaptation efforts are needed to avoid the most severe impacts of climate change