Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As part of an effort to inhibit S100B, structures of pentamidine (Pnt) bound to Ca(2+)-loaded and Zn(2+),Ca(2+)-loaded S100B were determined by X-ray crystallography at 2.15 A (R(free)=0.266) and 1.85 A (R(free)=0.243) resolution, respectively. These data were compared to X-ray structures solved in the absence of Pnt, including Ca(2+)-loaded S100B and Zn(2+),Ca(2+)-loaded S100B determined here (1.88 A; R(free)=0.267). In the presence and absence of Zn(2+), electron density corresponding to two Pnt molecules per S100B subunit was mapped for both drug-bound structures. One Pnt binding site (site 1) was adjacent to a p53 peptide binding site on S100B (+/-Zn(2+)), and the second Pnt molecule was mapped to the dimer interface (site 2; +/-Zn(2+)) and in a pocket near residues that define the Zn(2+) binding site on S100B. In addition, a conformational change in S100B was observed upon the addition of Zn(2+) to Ca(2+)-S100B, which changed the conformation and orientation of Pnt bound to sites 1 and 2 of Pnt-Zn(2+),Ca(2+)-S100B when compared to Pnt-Ca(2+)-S100B. That Pnt can adapt to this Zn(2+)-dependent conformational change was unexpected and provides a new mode for S100B inhibition by this drug. These data will be useful for developing novel inhibitors of both Ca(2+)- and Ca(2+),Zn(2+)-bound S100B.
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PMID:Divalent metal ion complexes of S100B in the absence and presence of pentamidine. 1860 2

p53 binds to some members of the S100 family (S100B, S100A4, S100A2, and S100A1). We previously showed that both S100B and S100A4 bind to the p53 tetramerization domain, and consequently control its oligomerization state, but only S100B binds to the C-terminal negative regulatory domain (NRD). Here, we investigate other binding partners for p53 within the S100 family (S100A6 and S100A11), and show that binding to the p53 tetramerization domain seems to be a general feature of the S100 family, while binding to the NRD is a characteristic of a subset of the family.
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PMID:Members of the S100 family bind p53 in two distinct ways. 1869 25

The members of the S100 protein family are multifunctional proteins with a regulatory role in a variety of cellular processes. They exert their actions usually through calcium binding, although Zn2+ and Cu2+ have also been shown to regulate their biological activity. The most studied member, protein S100B, exhibits neurotrophic (at physiologic concentration) or neurotoxic (at higher concentration) activity and its immunohistochemical expression or serum levels have been determined in various clinical disorders. S100B has been well documented as a marker of astrocytic activation mediating its effects via interaction with receptor for advanced glycation end products (RAGE). We herein provide a wide range of information concerning their clinical application in traumatic brain injuries, Alzheimer disease, subarachnoid haemorrhage and other neurologic disorders, malignant melanoma and several other neoplasms (as S100B has been shown to down-regulate p53), as well as inflammatory diseases. Also its use on predicting neurologic outcome after resuscitation for cardiac arrest or in intrauterine growth retardation newborns is discussed.
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PMID:S100 protein family and its application in clinical practice. 1915 63

Intrinsically disordered proteins (IDPs) are functional proteins where a lack of stable tertiary structures is required for function. Many of the IDPs involved in cellular regulation and signaling have substantial residual structures in the unbound state and fold into stable structures upon binding to their biological partners. Specific roles of these residual structures in and the underlying mechanisms of coupled binding and folding are poorly understood. Here we use physics-based atomistic simulations to compute the multidimensional free energy surfaces of coupled folding and binding of the intrinsically disordered p53 extreme C-terminus to protein S100B(betabeta). The results show that, even though the unbound p53 peptide appears to sample several alternative folded states previously observed when in complex with various targets, it binds to S100B(betabeta) through formation of nonspecific complexes, i.e., a "fly-casting"-like process. The current work, together with previous NMR and coarse-grained modeling studies of another prototypical system, suggests that the main role of the residual structures in the unbound states of regulatory IDPs might be to provide thermodynamic control of binding through modulating the entropic cost of folding and not to enhance the binding rate by acting as initial contact sites.
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PMID:Intrinsically disordered p53 extreme C-terminus binds to S100B(betabeta) through "fly-casting". 1921 10

We investigated the ways S100B, S100A1, S100A2, S100A4, and S100A6 bind to the different oligomeric forms of the tumor suppressor p53 in vitro, using analytical ultracentrifugation and multiangle light scattering. It is established that members of the S100 protein family bind to the tetramerization domain (residues 325-355) of p53 when it is uncovered in the monomer, and so binding can disrupt the tetramer. We found a stoichiometry of one dimer of S100 bound to a monomer of p53. We discovered that some S100 proteins could also bind to the tetramer. S100B bound the tetramer and also disrupted the dimer by binding monomeric p53. S100A2 bound monomeric p53 as well as tetrameric, whereas S100A1 only bound monomeric p53. S100A6 bound more tightly to tetrameric than to monomeric p53. We also identified an additional binding site for S100 proteins in the transactivation domain (1-57) of p53. Based on our results and published observations in vivo, we propose a model for the binding of S100 proteins to p53 that can explain both activation and inhibition of p53-mediated transcription. Depending on the concentration of p53 and the member of the S100 family, binding can alter the balance between monomer and tetramer in either direction.
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PMID:Modulation of the oligomerization state of p53 by differential binding of proteins of the S100 family to p53 monomers and tetramers. 1929 17

The binding of S100B to p53 disables the biological function of p53 as a tumor suppressor and thus causes cancer. It is very important to explore the interaction between S100B and p53 and to develop inhibitors to block the interaction in anti-cancer development. In this work, the interaction of S100B to p53 was studied using molecular dynamics (MD) at the atomic level and organic molecules have been identified as potential inhibitors to block the S100B-p53 interaction. It was indicated in the simulations that S100B residues around GLU45 and GLU46 play an important role in the binding of S100B to p53. The three dimensional structure of S100B obtained from S100B-p53 complex (PDB ID: 1DT7) was used as the target protein receptor. Multiple LUDI screenings for S100B ligands were performed using different searching radii 6.23 A, 7.23 A, 8.23 A, 9.23 A and 10.23A with a searching center which was defined as the geometrical center of S100B residues that are within 5A from the p53 C-terminal peptide in the complex. Potential organic compounds were screened from the ZINC database using LUDI program implemented in Cerius2 package and evaluated as potential S100B ligands to block the S100B-p53 interaction. The top-scored compounds were selected for binding affinity calculation. The results show that these top-scored ZINC compounds bind in the location where p53 binds and interact with S100B in a similar fashion as p53, and therefore it is expected that they have the potential to block S100B from binding to p53. The ADME and toxicity properties of the potential S100B ligands were also evaluated.
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PMID:Computational screening and design of S100B ligand to block S100B-p53 interaction. 1932 80

Structural studies are part of a rational drug design program aimed at inhibiting the S100B-p53 interaction and restoring wild-type p53 function in malignant melanoma. To this end, structures of three compounds (SBi132, SBi1279, and SBi523) bound to Ca(2+)-S100B were determined by X-ray crystallography at 2.10 A (R(free) = 0.257), 1.98 A (R(free) = 0.281), and 1.90 A (R(free) = 0.228) resolution, respectively. Upon comparison, SBi132, SBi279, and SBi523 were found to bind in distinct locations and orientations within the hydrophobic target binding pocket of Ca(2+)-S100B with minimal structural changes observed for the protein upon complex formation with each compound. Specifically, SBi132 binds nearby residues in loop 2 (His-42, Phe-43, and Leu-44) and helix 4 (Phe-76, Met-79, Ile-80, Ala-83, Cys-84, Phe-87, and Phe-88), whereas SBi523 interacts with a separate site defined by residues within loop 2 (Ser-41, His-42, Phe-43, Leu-44, Glu-45, and Glu-46) and one residue on helix 4 (Phe-87). The SBi279 binding site on Ca(2+)-S100B overlaps the SBi132 and SBi523 sites and contacts residues in both loop 2 (Ser-41, His-42, Phe-43, Leu-44, and Glu-45) and helix 4 (Ile-80, Ala-83, Cys-84, Phe-87, and Phe-88). NMR data, including saturation transfer difference (STD) and (15)N backbone and (13)C side chain chemical shift perturbations, were consistent with the X-ray crystal structures and demonstrated the relevance of all three small molecule-S100B complexes in solution. The discovery that SBi132, SBi279, and SBi523 bind to proximal sites on Ca(2+)-S100B could be useful for the development of a new class of molecule(s) that interacts with one or more of these binding sites simultaneously, thereby yielding novel tight binding inhibitors specific for blocking protein-protein interactions involving S100B.
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PMID:Small molecules bound to unique sites in the target protein binding cleft of calcium-bound S100B as characterized by nuclear magnetic resonance and X-ray crystallography. 1946 84

As a tumor suppressor, p53 plays an important role in cancer suppression. The biological function of p53 as a tumor suppressor is disabled when it binds to S100B. Developing the ligands to block the S100B-p53 interaction has been proposed as one of the most important approaches to the development of anti-cancer agents. We screened a small compound library against the binding interface of S100B and p53 to identify potential compounds to interfere with the interaction. The ligand-binding effect on the S100B-p53 interaction was explored by molecular dynamics at the atomic level. The results show that the ligand bound between S100B and p53 propels the two proteins apart by about 2 A compared to the unligated S100B-p53 complex. The binding affinity of S100B and p53 decreases by ~8.5-14.6 kcal/mol after a ligand binds to the interface from the original unligated state of the S100B-p53 complex. Ligand-binding interferes with the interaction of S100B and p53. Such interference could impact the association of S100B and p53, which would free more p53 protein from the pairing with S100B and restore the biological function of p53 as a tumor suppressor. The analysis of the binding mode and ligand structural features would facilitate our effort to identify and design ligands to block S100B-p53 interaction effectively. The results from the work suggest that developing ligands targeting the interface of S100B and p53 could be a promising approach to recover the normal function of p53 as a tumor suppressor.
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PMID:Molecular dynamics simulation of S100B protein to explore ligand blockage of the interaction with p53 protein. 1959 41

Proteins of the S100 family bind to the intrinsically disordered transactivation domain (TAD; residues 1-57) and C-terminus (residues 293-393) of the tumor suppressor p53. Both regions provide sites that are subject to posttranslational modifications, such as phosphorylation and acetylation, that can alter the affinity for interacting proteins such as p300 and MDM2. Here, we found that S100A1, S100A2, S100A4, S100A6, and S100B bound to two subdomains of the TAD (TAD1 and TAD2). Both subdomains were mandatory for high-affinity binding to S100 proteins. Phosphorylation of Ser and Thr residues increased the affinity for the p53 TAD. Conversely, acetylation and phosphorylation of the C-terminus of p53 decreased the affinity for S100A2 and S100B. In contrast, we found that nitrosylation of S100B caused a minor increase in binding to the p53 C-terminus, whereas binding to the TAD remained unaffected. As activation of p53 is usually accompanied by phosphorylation and acetylation at several sites, our results suggest that a shift in binding from the C-terminus in favor of the N-terminus occurs upon the modification of p53. We propose that binding to the p53 TAD might be involved in the stimulation of p53 activity by S100 proteins.
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PMID:Posttranslational modifications affect the interaction of S100 proteins with tumor suppressor p53. 1981 44

S100A1 is a member of the S100 family of calcium-binding proteins. As with most S100 proteins, S100A1 undergoes a large conformational change upon binding calcium as necessary to interact with numerous protein targets. Targets of S100A1 include proteins involved in calcium signaling (ryanidine receptors 1 & 2, Serca2a, phopholamban), neurotransmitter release (synapsins I & II), cytoskeletal and filament associated proteins (CapZ, microtubules, intermediate filaments, tau, mocrofilaments, desmin, tubulin, F-actin, titin, and the glial fibrillary acidic protein GFAP), transcription factors and their regulators (e.g. myoD, p53), enzymes (e.g. aldolase, phosphoglucomutase, malate dehydrogenase, glycogen phosphorylase, photoreceptor guanyl cyclases, adenylate cyclases, glyceraldehydes-3-phosphate dehydrogenase, twitchin kinase, Ndr kinase, and F1 ATP synthase), and other Ca2+-activated proteins (annexins V & VI, S100B, S100A4, S100P, and other S100 proteins). There is also a growing interest in developing inhibitors of S100A1 since they may be beneficial for treating a variety of human diseases including neurological diseases, diabetes mellitus, heart failure, and several types of cancer. The absence of significant phenotypes in S100A1 knockout mice provides some early indication that an S100A1 antagonist could have minimal side effects in normal tissues. However, development of S100A1-mediated therapies is complicated by S100A1's unusual ability to function as both an intracellular signaling molecule and as a secreted protein. Additionally, many S100A1 protein targets have only recently been identified, and so fully characterizing both these S100A1-target complexes and their resulting functions is a necessary prerequisite.
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PMID:S100A1: Structure, Function, and Therapeutic Potential. 1989 Apr 75


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