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Structural bases of aptamer-thrombin recognition
No full textIllustration of the modulation of human alpha thrombin activity by DNA-aptamers adopting G-quadruplex structures
A Crystallographic Approach for Understanding the Recognition Mechanism of Thrombin and G-quadruplex Aptamers
No full textHuman-thrombin, a serine protease that maintains blood hemostasis by balancing pro- and anti-coagulant actions is an example of protein with multiple binding sites1. In addition to the active site, the enzyme possesses two electropositive regions, in near-opposition on the protein surface, known as exosite I and exosite II, respectively. These two regions have a primary role in the regulation of enzymatic activity since they can bind molecules with diverse functions2-4. Given its central role in the clot formation, thrombin is an attractive target for the development of agents that effectively interfere with thrombogenesis. A special class of thrombin synthetic ligands is represented by nucleic acid aptamers adopting G-quadruplex structures. HD1, a 15-mer oligonucleotide recognizing exosite I5, and HD22, a 29-mer binding exosite II6, are the most studied thrombin binding aptamers and show high affinity toward their target (Kd (HD1)≈ 100 nM; Kd(HD22) ≈0.7 nM). The increased interest in the use of DNA aptamers as drugs has stimulated the search of HD1 and HD22 variants with improved properties. In particular, the bimodular oligonucleotides RE317 and NU1728, which have been obtained by addition of a duplex motif to the HD1 quadruplex module, show higher affinity for thrombin and anticoagulant activity, and a slower disappearance rate in human plasma in comparison with HD1.
Here I will present the most relevant results regarding the elucidation of the interactions, which govern the recognition between thrombin and DNA G-quadruplex aptamers9-14
Structural Motifs governing thrombin-aptamer recognition
No full textIllustrazione dei motivi strutturali che governano il riconoscimento molecolare tra l'alpha trombina umana ed i suoi aptameri a DN
Structural overview of DNA and RNA G-quadruplexes in their interaction with proteins
No full text: Since the discovery of G-quadruplex (G4) participation in vital cellular processes, the regulation of the interaction of naturally occurring G4s with the relative target proteins has emerged as a promising approach for therapeutic development. Additionally, a synthetic strategy has produced several oligonucleotide aptamers, embodying a G4 module, which exhibit relevant biological activity by binding selectively to a target protein. In this context, the G4-protein structures available in the Protein Data Bank represent a valuable molecular view of the different G4 topologies involved in protein interaction. Interestingly, recent results have shown the co-existence of G4s with other structural domains such as duplexes. Overall, these findings allow a better understanding of the mechanisms that regulate intricate biological functions and suggest new design for innovative medical treatments
ANALISI STRUTTURALE DI FORME MONOMERICHE ED AGGREGATE DI RIBONUCLEASI DI TIPO PANCREATICO
No full textVengono affrontati gli aspetti strutturali allo stato solido ed in soluzione di derivati della ribonucleasi bovina seminale. La forma monomerica ottenuta per riduzione selettiva dei disolfuri intercatena e successiva protezione, è stata cristallizzata nella forma libera e complessata con un inibitore nucleotidico. Essa rappresenta la prima struttura di una forma senza interscambio dei tratti N-terminali, che invece si verifica nel dimero naturale. Nelle parti conclusive le strutture ottenute sono discusse in relazione alle proprietà antitumorali dell'enzima seminale
Mapping dell’Epitopo di un immunoreagente antitumorale anti-ErbB2: un approccio computazionale
No full textIdentification of Aminosuccinyl Residues In Peptides By 2nd-derivative Ultraviolet Spectrometry
No full textApproximate Values for Force Constant and Wave Number Associated with a Low-Frequency Concerted Motion in Proteins Can Be Evaluated by a Comparison of X-ray Structures.
No full textLow-frequency internal motions in protein molecules play a key role in biological functions. A direct relationship between low-frequency motions and enzymatic activity has been suggested for bovine pancreatic ribonuclease (RNase A). The flexibility-function relationship in this enzyme has been attributed to a subtle and concerted breathing motion of the beta-sheet regions occurring upon substrate binding and release. Here, we calculate an approximate value for the force constant and the wave number of the low-frequency beta-sheet breathing motion of RNase A, by using the Boltzmann hypothesis on a set of data derived from a simple conventional structural superimposition of an unusual large number of X-ray structures available for the protein. The results agree with previous observations and with theoretical predictions on the basis of normal-mode analysis. To the best of our knowledge, this is the first example in which the wave number and the force constant of a low-frequency concerted motion in a protein are directly derived from X-ray structures
L-aspartyl(beta-benzyl Ester)glycylglycine Methyl-ester Trifluoroacetic-acid [l-asp(beta-bzl)-gly-gly-ome.tfa]
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