9ifx | pdb_00009ifx
Beta-hairpin macrocyclic peptide in complex with STAT1
Structural highlights
DiseaseSTAT1_HUMAN Defects in STAT1 are the cause of STAT1 deficiency complete (STAT1D) [MIM:613796. STAT1D is a disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness.[1] [2] Defects in STAT1 are a cause of Mendelian susceptibility to mycobacterial disease (MSMD) [MIM:209950; also known as familial disseminated atypical mycobacterial infection. This rare condition confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. The pathogenic mechanism underlying MSMD is the impairment of interferon-gamma mediated immunity whose severity determines the clinical outcome. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance.[3] [4] [5] Defects in STAT1 are the cause of familial candidiasis type 7 (CANDF7) [MIM:614162. A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. Note=STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin-17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa (PubMed:21714643).[6] [7] FunctionSTAT1_HUMAN Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated. It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.[8] [9] [10] [11] [12] Publication Abstract from PubMedMimicry of protein secondary structure elements, such as alpha-helices and beta-sheets, using conformationally constrained peptide macrocycles, can be utilized to disrupt native protein-protein and protein-nucleic acid interactions. Although alpha-helical stapled peptides have been extensively studied as pharmacological probes, the application of beta-sheet and beta-hairpin mimetics remains comparatively limited. Less is known about the structural and biophysical consequences of beta-hairpin macrocyclization in the context of target binding. In this work, we use a poxvirus immune antagonist protein 018 as a template for the structure-based design of beta-hairpin mimetic macrocyclic peptides targeting the STAT1 transcription factor. We demonstrate that successive orthogonal cyclizations have additive effects on the thermodynamic and kinetic properties of peptide binding, most notably slowing the dissociation from the target. We elucidate the structural and dynamic consequences of interstrand and head-to-tail cross-linking and propose a kinetic model explaining the gains in target residence. Finally, we highlight the pharmacological potential of these peptides by competitive inhibition of STAT1 binding to its cognate interferon receptor docking site. These data suggest that beta-hairpin macrocyclization may represent a general strategy to extend target engagement, with implications for peptidic probe design. Consequences of Peptide Macrocyclization Revealed by Virus-Inspired beta-Hairpin Mimetics.,Bula AL, Bobrovs R, Arsenyan P, Pantelejevs T ACS Chem Biol. 2026 Jan 16;21(1):160-169. doi: 10.1021/acschembio.5c00834. Epub , 2025 Dec 22. PMID:41427528[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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