Direct and Allosteric Inhibition of the FGF2/HSPGs/FGFR1 Ternary Complex Formation by an Antiangiogenic, Thrombospondin-1-Mimic Small Molecule

Pagano, Katiuscia; Torella, Rubben; Foglieni, Chiara; Bugatti, Antonella; Tomaselli, Simona; Zetta, Lucia; Presta, Marco; Rusnati, Marco; Taraboletti, Giulia; Colombo, Giorgio; Ragona, Laura

doi:10.1371/journal.pone.0036990

Cited by 39 publications

(71 citation statements)

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“…Previous studies had identified the small molecule sm27 as a mimic of the FGF2-binding sequence of thrombospondin-1 able to engage the heparin-binding site of FGF2 (Pagano et al, 2012). As observed for other anionic compounds (Presta et al, 2005), sm27 may interact with the heparin-binding domain of a variety of signaling proteins with possible unsought side effects.…”

Section: Discussionmentioning

confidence: 93%

Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

et al. 2015

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The fibroblast growth factor (FGF)/FGF receptor (FGFR) system plays a crucial role in cancer by affecting tumor growth, angiogenesis, drug resistance, and escape from anti-angiogenic anti-vascular endothelial growth factor therapy. The soluble pattern recognition receptor long-pentraxin 3 (PTX3) acts as a multi-FGF antagonist. Here we demonstrate that human PTX3 overexpression in transgenic mice driven by the Tie2 promoter inhibits tumor growth, angiogenesis, and metastasis in heterotopic, orthotopic, and autochthonous FGF-dependent tumor models. Using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2, we identified a small-molecule chemical (NSC12) that acts as an extracellular FGF trap with significant implications in cancer therapy.

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Section: Discussionmentioning

confidence: 93%

Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

et al. 2015

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“…Such an approach was recently attempted for Hsp70 by Nicolai et al [21] with the aim of defining the dynamic modes involved in the transition. With a complementary point of view, in this paper we have applied a set of recently developed methods [15], [16], [17], [18] that allow us to identify the relevant residues which are involved in the early onset of a conformational change in DnaK. We comparatively analyze the structural and dynamical changes that occur at the single residue level on the ns scale and relate these to the complete conformational transition.…”

Section: Discussionmentioning

confidence: 99%

“…By simulating several protein-nucleotide complexes in a fully solvated environment and applying a set of structural and dynamical analyses specifically developed for the study of allosteric systems [15], [16], [17], [18], we aim to gain insights into the mechanisms of nucleotide-induced signal propagation in Hsp70 and identify functional hotspots involved in the response to ATP and ADP in different conformational states of the protein. To this end, we simulated multiple MD trajectories of Hsp70 and Hsp110 proteins in complex with ATP, ADP and in the apo form (total simulation time: 1.9 microseconds).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations

et al. 2012

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Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.

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“…Owing to the high spin-lock field, offset errors (the highest offset <800 Hz) in R 1ρ -to-R 2 conversion were neglected, and R 1ρ was assumed to estimate R 2 according to ref. 65. The apparent exchange contribution, R ex , was then estimated as the difference between R 2 and R 1ρ .…”

Section: Competing Financial Interestsmentioning

confidence: 99%

Cooperative structure of the heterotrimeric pre-mRNA retention and splicing complex

Wysoczanski

Schneider

Munari

et al. 2014

Nat Struct Mol Biol

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1 1 a r t i c l e sSplicing entails the removal of introns from pre-mRNAs to generate exon-only mRNA, which is exported out of the nucleus for translation 1 . The splicing process is driven and controlled by a large and dynamic RNA-protein complex, the spliceosome 1,2 . The composition and structure of the spliceosome undergoes multiple rearrangements during a splicing reaction, in which a set of distinct structural and compositional states, designated as E, A, B act , B* and C complexes, can be defined 1 . As part of this process, small nuclear ribonucleoprotein (snRNP) particles and non-snRNP splice factors are recruited and released 1,2 . Although the organization of snRNP components of the spliceosome has received considerable attention in recent years, very little is known about the assembly, structure and dynamics of non-snRNP multimeric complexes.The non-snRNP RES complex is present in humans and yeast 3,4 . Deletion of RES genes slows splicing and leads to pre-mRNA leakage into the cytoplasm 3-5 . Distinct introns exhibit RES-dependent splicing 5-9 , as do pre-mRNAs encoding proteins functioning in RNA-nucleotide metabolism 8,10 . Components of the RES complex are found in B and C complexes of the spliceosome, in which RES can interact with U2 snRNP 4,11,12 . In yeast, the RES complex is composed of three proteins, snRNP-associated protein 17 (Snu17p, also known as Ist3p), pre-mRNA-leakage protein 1 (Pml1p) and bud siteselection protein 13 (Bud13p) 3,4 . Snu17p and Bud13p have been implicated directly in splicing 3,5,13 , whereas Pml1p has been linked to the retention of unspliced pre-mRNA in the nucleus 3,5 . Caenorhabditis elegans Bud13p is involved in embryogenesis 14 .Sequence analysis has indicated that Snu17p is a 148-residue (17.1-kDa) noncanonical member of the RRM family of proteins with a long C-terminal part, which exhibits low sequence similarity to published RRM structures 4 . Snu17p binds with nanomolar affinity to the 266-residue (30.5-kDa), natively disordered protein Bud13p 15 . The interaction has been postulated to involve a C-terminal UHM-ligand motif (ULM) in Bud13p that interacts with a U2AF-homology motif (UHM) in the RRM domain of Snu17p 13,15,16 . The only other identified domain encompasses a stretch of lysine residues at the N terminus of Bud13p. Binding of the third component, the 204-residue (23.4-kDa) Pml1p, occurs through its 50 N-terminal disordered residues. The remainder of Pml1p folds as a forkhead-associated domain 13,15,17 , which could potentially bind phosphopeptides 17 . Biochemical evidence has suggested that Snu17p acts as the central binding platform, which interacts with disordered parts of Bud13p and Pml1p 13,15,16 . The precise molecular architecture of the RES complex, however, has been elusive, and its RNA binding capabilities have remained unexplored.Here we solved the three-dimensional structure of the core of the RES complex and demonstrated that its assembly is driven by cooperativity that increases the binding affinity of the components of the complex ...

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Direct and Allosteric Inhibition of the FGF2/HSPGs/FGFR1 Ternary Complex Formation by an Antiangiogenic, Thrombospondin-1-Mimic Small Molecule

Cited by 39 publications

References 50 publications

Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations

Cooperative structure of the heterotrimeric pre-mRNA retention and splicing complex

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