General Information

Database accession: MF7000599

Name: S100A13 with a drug amlexanox

PDB ID: 2kot PDBe

Experimental method: NMR

Assembly: Homodimer

Source organism: Homo sapiens

Primary publication of the structure:

Rani SG, Mohan SK, Yu C
Molecular level interactions of S100A13 with amlexanox: inhibitor for formation of the multiprotein complex in the nonclassical pathway of acidic fibroblast growth factor.
(2010) Biochemistry 49: 2585-92

PMID: 20178375 PubMed

Abstract:

S100A13 and acidic fibroblast growth factor (FGF1) are involved in a wide array of important biological processes, such as angiogenesis, cell differentiation, neurogenesis, and tumor growth. Generally, the biological function of FGF1 is to recognize a specific tyrosine kinase on the cell surface and initiate the cell signal transduction cascade. Amlexanox (2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid) is an antiallergic drug that binds S100A13 and FGF1 and inhibits the heat shock induced release of S100A13 and FGF1. In the present study, we investigated the interaction of amlexanox with S100A13 using various biophysical techniques, including isothermal titration calorimetry, fluorescence spectrophotometry, and multidimensional NMR spectroscopy. We report the three-dimensional solution structure of the S100A13-amlexanox complex. These data show that amlexanox binds specifically to the FGF1-S100A13 interface and prevents the formation of the FGF1-releasing complex. In addition, we demonstrate that amlexanox acts as an antagonist of S100A13 by binding to its FGF1 binding site and subsequently inhibiting the nonclassical pathway of these proteins. This inhibition likely results in the ability of amlexanox to antagonize the angiogenic and mitogenic activity of FGF1.


Function and Biology Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown.

Molecular function:

calcium ion binding calcium ion binding GeneOntology

calcium-dependent protein binding calcium-dependent protein binding GeneOntology

copper ion binding copper ion binding GeneOntology

fibroblast growth factor binding fibroblast growth factor binding GeneOntology

lipid binding lipid binding GeneOntology

protein homodimerization activity protein homodimerization activity GeneOntology

RAGE receptor binding RAGE receptor binding GeneOntology

zinc ion binding zinc ion binding GeneOntology

Biological process:

mast cell degranulation mast cell degranulation GeneOntology

positive regulation of canonical NF-kappaB signal transduction positive regulation of canonical NF-kappaB signal transduction GeneOntology

positive regulation of cell population proliferation positive regulation of cell population proliferation GeneOntology

positive regulation of cytokine production positive regulation of cytokine production GeneOntology

positive regulation of interleukin-1 alpha production positive regulation of interleukin-1 alpha production GeneOntology

protein transport protein transport GeneOntology

Cellular component:

cytoplasm cytoplasm GeneOntology

cytosol cytosol GeneOntology

extracellular region extracellular region GeneOntology

extracellular space extracellular space GeneOntology

nucleolus nucleolus GeneOntology

nucleoplasm nucleoplasm GeneOntology

nucleus nucleus GeneOntology

perinuclear region of cytoplasm perinuclear region of cytoplasm GeneOntology

plasma membrane plasma membrane GeneOntology

Structure Summary Structural annotations of the participating protein chains.

Entry contents: 2 distinct polypeptide molecules

Chains: A, B

Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.

Number of unique protein segments: 1


Chain A

Name: Protein S100-A13

Source organism: Homo sapiens

Length: 98 residues

Sequence:Sequence according to the corresponding UniProt protein segmentMAAEPLTELEESIETVVTTFFTFARQEGRKDSLSVNEFKELVTQQLPHLLKDVGSLDEKMKSLDVNQDSELKFNEYWRLIGELAKEIRKKKDLKIRKK

UniProtKB AC: Q99584 (positions: 1-98) UniProt

Coverage: 100%

Chain B

Name: Protein S100-A13

Source organism: Homo sapiens

Length: 98 residues

Sequence:Sequence according to the corresponding UniProt protein segmentMAAEPLTELEESIETVVTTFFTFARQEGRKDSLSVNEFKELVTQQLPHLLKDVGSLDEKMKSLDVNQDSELKFNEYWRLIGELAKEIRKKKDLKIRKK

UniProtKB AC: Q99584 (positions: 1-98) UniProt

Coverage: 100%

Evidence Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding.

Representative domain in related structures: S-100/ICaBP type EF hand dimer

Evidence level: Direct evidence

Evidence coverage: The full structure participates in mutual synergistic folding.

Complex Evidence:

GuHCl-induced denaturation of the S100B protein dimer showed that it follows a two-state unfolding/refolding process (PMID:11888280). Other S100 proteins also showed two-state unfolding, no folded monomers were observed (PMID:18346834, PMID:18706914). The dimer has a globular and compact structure with the four helices in each subunit aligning to form a unicornate-type four-helix bundle (PMID:11790100). The hydrophobic core extends through the dimer interface.

Chain A:

N/A

Chain B:

N/A

Surface and contacts features:

Related Structure(s) Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap).

There are 37 related structures in the MFIB database:






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