Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation-π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage

Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines chondrogenic differentiation

Contains fulltext : 177137.pdf (publisher's version ) (Open Access)15 p

Anti‐cyclic citrullinated peptide positivity in non‐rheumatoid arthritis disease samples: citrulline‐dependent or not?

BACKGROUND: Antibodies directed against citrullinated proteins (eg anti‐cyclic citrullinated peptide (CCP)) have excellent diagnostic and good prognostic potential for rheumatoid arthritis. Type 1 autoimmune hepatitis (AIH‐1) is a chronic liver disease characterised by a variety of serum autoantibodies. Recently, in a large group of patients with AIH‐1 without clear rheumatoid arthritis overlap, a relatively high percentage (9%) of anti‐CCP2 positivity was scored. OBJECTIVES: To characterise the citrulline‐dependence of the observed anti‐CCP2 positivity in AIH‐1 sera as well as in other groups of patients without rheumatoid arthritis (mainly rheumatic diseases). METHODS: Serum samples of 57 patients with AIH‐1 and 66 patients without rheumatoid arthritis, most of them reported as anti‐CCP positive, were tested for citrulline‐specific reactivity with a second generation anti‐CCP kit, with the citrullinated and the corresponding non‐citrullinated (arginine‐containing) antigen. A subset of AIH‐1 sera was also tested with a CCP1 ELISA (and arginine control). RESULTS: The anti‐CCP2 reactivity of most non‐rheumatoid arthritis rheumatic diseases samples (87–93%) was citrulline‐specific, whereas a relatively high percentage of AIH‐1 samples (42–50%) turned out to be reactive in a citrulline‐independent manner. The use of citrullinated and non‐citrullinated CCP1 peptides confirmed a high occurrence of citrulline‐independent reactivity in AIH‐1 samples. CONCLUSIONS: In rheumatoid arthritis and most non‐rheumatoid arthritis rheumatologic disease sera, anti‐CCP positivity is citrulline‐dependent. However in some patients, particularly patients with AIH‐1, citrulline‐independent reactivity in the anti‐CCP2 test can occur. A positive CCP test in a non‐rheumatic disease (eg liver disease) should therefore be interpreted with care, and preferably followed by a control ELISA with a non‐citrullinated antigen

Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides

Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay