Publications by authors named "P J Beltran"
Despite the widespread use of MS for hydrogen/deuterium exchange measurements, no systematic, large-scale study has been conducted to compare the observed exchange rates in protein-derived, unstructured peptides measured by MS to the predicted exchange rates calculated from NMR-derived values and how neighboring residues and post-translational modifications influence those exchange rates. In this study, we sought to test the accuracy of predicted values by performing hydrogen exchange measurements on whole cell digests to generate an unbiased dataset of 563 unique peptides derived from naturally-occurring protein sequences. A remarkable 97% of observed exchange rates of peptides are within two-fold of predicted values.
View Article and Find Full Text PDFApproved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON).
View Article and Find Full Text PDFCompromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME.
View Article and Find Full Text PDFArticle Synopsis
- Oncogenic KRAS mutants show different biochemical behaviors due to their unique conformations; they exist in two primary states, active (state 2) and inactive (state 1), which are influenced by how they bind to molecules like GTP and GppNHp.
- Research using P NMR has revealed that KRAS bound to GTP primarily adopts the active state (over 90% in state 2), while GppNHp-bound KRAS shows a significant population in the inactive state 1, a condition likely not seen in living cells.
- A new small-molecule inhibitor, BBO-8956, has been developed that targets KRAS G12C and disrupts the state 1-state
Article Synopsis
- Chromosomal instability (CIN) is a common feature in aggressive cancers, such as high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC), often linked to TP53 mutations.
- Researchers discovered that KIF18A motor protein inhibitors can activate the mitotic checkpoint, causing selective death of cancer cells with CIN, especially those with TP53 mutations.
- These inhibitors demonstrated minimal side effects on normal human bone marrow cells and showed significant tumor regression in HGSOC and TNBC models in mice, suggesting a promising targeted therapy for CIN-associated cancers.