1,721,100 research outputs found
IN SILICO AND IN VITRO VALIDATION OF SERINE HYDROXYMETHYLTRANSFERASE AS A CHEMOTHERAPEUTIC TARGET OF THE ANTIFOLATE DRUG PEMETREXED.
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Riconoscimento alla carriera scientifica assegnato a un giovane ricercatore della Sapienza dal Presidente della Repubblica Italiana
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EVOLUZIONE MOLECOLARE E VERSATILITA' STRUTTURALE DEGLI ENZIMI DIPENDENTI DAL PIRIDOSSALE-5'-FOSFATO CON RIPIEGAMENTO DI TIPO I
Full text linkMaurizio Paci, Giovanni Antonini, Nazzareno Capitani
Insights into the interaction of sortilin with proneurotrophins: A computational approach
No full textSortilin is a member of the recently discovered family of type-1 transmembrane Vps10p-domain receptors, which are expressed in several tissues, including brain and spinal chord. It has been recently demonstrated that the interaction between sortilin and the N-terminal portion of the precursor forms of the nerve growth factor (pro-NGF) and the brain-derived neurotrophic factor (pro-BDNF) represents a key event in the process that controls neurotrophins-mediated cell survival and death in developing neuronal tissue and post-traumatic neuronal apoptosis. Moreover, it is known that the cleavage of the N-terminal propeptide of sortilin is required for full functional activity of the receptor. The propeptide, indeed, hinders ligands from accessing the binding site of sortilin. However, to date, the molecular mechanism underlying the interaction between sortilin and pro-NGF/pro-BDNF remains unknown. By means of computational approaches, we suggest that the N-terminal Vps10p domain of sortilin, which is responsible for the interaction with the neurotrophins, adopts a beta-propeller fold, and that the N-terminal regions of sortilin, pro-NGF and pro-BDNF are mainly intrinsically disordered regions (IDRs). The following mechanism is therefore proposed: the Vps10p-domain of sortilin is a beta-propeller able to bind its own IDR and the IDRs of neurotrophins. The excision of its N-terminal disordered peptide allows the interaction with the intrinsically disordered N-terminus of pro-BDNF and pro-NGF, possibly through a disorder-to-order transition behaviour. (c) 2007 Elsevier Ltd. All rights reserved
Bioinformatica: dalla sequenza alla struttura delle proteine
No full textl connubio tra biologia e informatica potrebbe apparire, in un primo momento, curioso. In realtà, la vita stessa può essere interpretata come un flusso continuo d’informazione, conservata attraverso il codice genetico e capace di plasmare la materia biologica nelle funzioni e nelle forme più svariate.
La bioinformatica, la disciplina che applica i principi della scienza dell’informazione alla biologia per rendere più comprensibile il complesso mondo delle scienze della vita, opera principalmente in tre ambiti:
la conservazione, l’organizzazione e la distribuzione di dati relativi agli esseri viventi;
lo sviluppo di metodologie e l’implementazione di algoritmi per l’indagine in campo biomedico;
l’utilizzo di tali strumenti per estrapolare informazione dai dati.
Questo manuale propone una panoramica delle tecniche bioinformatiche utili per affrontare l’analisi di proteine (bioinformatica strutturale), introduce lo studente alla logica di funzionamento dei programmi più usati e dedica un capitolo alla programmazione in Python, un linguaggio emergente per la bioinformatica. Contiene inoltre numerosi link e riferimenti a risorse liberamente accessibili sul web, che permettono di utilizzare immediatamente molti dei metodi descritti
A 3D model of Reelin subrepeat regions predicts Reelin binding to carbohydrates
No full textReelin is a large molecule of the extracellular matrix (ECM) which regulates neuronal positioning during the early stages of cortical development in vertebrate species. The Reelin molecule can be subdivided into a smaller N-terminal domain, showing homology with F-spondin, and a larger C-terminal region containing 8 EGF-like repeats. The localization of Reelin in the ECM, its large dimensions and the modular organization of its primary structure led us to suppose a structure of its modules similar to domains commonly found in ECM proteins such as Agrin, laminins and thrombospondins. We therefore performed a sequence alignment and molecular modeling analysis to study the three-dimensional fold of the Reelin subrepeat regions. Our analysis produces a tentative model of the core region of the Reelin subrepeat sequences and suggests the presence in this 3D model of structural features common to polysaccharide-binding modules which are often found on proteoglycans of the ECM. These findings provide a conceptual framework for further experiments aimed at testing the functions of the EGF-like repeat regions of Reelin. (c) 2006 Elsevier B.V. All rights reserved
Structurally conserved regions and hydrophobic contacts in the fold type I, PLP-dependent enzymes
No full textINTRODUCTION: The interacting hydrophobic residues conserved at primary and tertiary structure levels have been investigated in the case of fold-type I, pyridoxal-5’- phosphate (PLP) dependent enzymes. Although there are at least five evolutionarily unrelated superfamilies of PLP-dependent enzymes, each displaying a completely different fold, the by far largest and best characterised is known as fold-type I, family, or aspartate aminotransferase family. This large group of enzymes, that are found in all organisms and cover together the whole range of enzymatic activities catalogued by the Enzyme Commission, bears several interesting characteristics: its members are highly divergent enzymes which display structural homology with almost undetectable sequence similarity; thanks to the recent massive sequencing of several genomes and advances in protein structure determination, a good wealth of experimentally well characterised information is now available for this superfamily. On the basis of such consideration, the present work was aimed at detecting the conserved structural patterns possibly responsible for the maintenance of the fold of this protein superfamily. The role played by conserved residues in the stabilisation of the native structure and their possible involvement in the mechanism of protein folding was then discussed in the light of the most recent studies on PLP-dependent enzymes.
MATERIAL AND METHODS: a non redundant set of 23 structures of PLP dependent enzymes of type I was collected from the databanks. An initial structural alignment was obtained with the program CE (1) and was subsequently refined by hand. Structurally Conserved Regions (SCR) were defined as those regions displaying similar local conformation (RMSD over superposed Cα atoms less than 3.0 Å), with no indel and at least three-residue long. Pairwise hydrophobic contact areas were calculated for every possible residue belonging to SCRs. The equivalent hydrophobic contacts present in most of the superposed structures were defined as Conserved Hydrophobic Contacts (CHC). Sequence homologs were collected from the databanks and, after a check for redundancy, aligned to the structural alignment for a total of 921 sequences.
RESULTS: Most of the sequences collected and aligned display pairwise sequence identity in the range 0%-20% which encompass the “twilight zone”. This suggest that the data set is suitable to explore distant evolutionary events. Fifteen CHCs involving 22 residues were collected at the end of the analysis. These CHCs can be grouped into three clusters: one is located in the proximity of the PLP molecule, the second in the minor domain, and the third in the hinge region between two SCRs (Figure 1). Seventeen out of the 22 residues involved in CHCs are highly conserved across the multiple alignment of 921 sequences. Sequence conservation whithin the SCRs has also been analysed. Eleven sites within the SCRs not involved in CHCs display a significant sequence conservation. These position can be grouped in two categories: i) Gly or Ala rich positions in the proximity of CHC residues and ii) positions involved in hydrophobic contacts that do not meet the criteria followed to define a significant CHC. The CHCs and the conserved positions within the SCRs suggest the existence of determinants necessary to the stabilization and the maintaining of the fold of the PLP type I enzymes. We suggest that this analysis can be extended to other families and can help planning experiments of protein folding and design
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