scholarly journals Implication of HLA-DMA Alleles in Corsican IDDM

1998 ◽  
Vol 14 (3) ◽  
pp. 135-141 ◽  
Author(s):  
P. Cucchi-Mouillot ◽  
S. Lai ◽  
C. Carcassi ◽  
P. Sorba ◽  
M. Stuart-Simoni ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Autoimmune Disease ◽  
Gene Polymorphism ◽  
Peptide Binding ◽  
Additional Tool ◽  
Classical Class ◽  
Antigen Peptide ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Peptide Exchange

The HLA-DM molecule catalyses the CLIP/antigen peptide exchange in the classical class II peptide-binding groove. As such, DM is an antigen presentation regulator and may be linked to autoimmune diseases. Using PCR derived methods, a relationship was revealed between DM gene polymorphism and IDDM, in a Corsican population. The DMA*0101 allele was observed to confer a significant predisposition to this autoimmune disease while the DMA*0102 allele protected significantly. Experiments examining polymorphism of the HLA-DRB1 gene established that these relationships are not a consequence of linkage disequilibrium with HLA-DRB1 alleles implicated in this pathology. The study of the DMA gene could therefore be an additional tool for early IDDM diagnosis in the Corsican population.

scholarly journals The strength of selection is consistent across both domains of the MHC class I peptide-binding groove in birds

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Piotr Minias ◽  
Ke He ◽  
Peter O. Dunn
Keyword(s):  
Mhc Class I ◽  
Peptide Binding ◽  
Variable Region ◽  
Molecular Data ◽  
Class I ◽  
Amino Acid Polymorphism ◽  
Exon 2 ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Avian Mhc

Abstract Background The Major Histocompatibility Complex (MHC) codes for the key vertebrate immune receptors responsible for pathogen recognition. Foreign antigens are recognized via their compatibility to hyper-variable region of the peptide-binding groove (PBR), which consists of two separate protein domains. Specifically, the PBR of the MHC class I receptors, which recognize intra-cellular pathogens, has two α domains encoded by exon 2 (α1) and exon 3 (α2) of the same gene. Most research on avian MHC class I polymorphism has traditionally focused exclusively on exon 3 and comparisons of selection between the two domains have been hampered by the scarcity of molecular data for exon 2. Thus, it is not clear whether the two domains vary in their specificity towards different antigens and whether they are subject to different selective pressure. Results Here, we took advantage of rapidly accumulating genomic resources to test for the differences in selection patterns between both MHC class I domains of the peptide-binding groove in birds. For this purpose, we compiled a dataset of MHC class I exon 2 and 3 sequences for 120 avian species from 46 families. Our phylogenetically-robust approach provided strong evidence for highly consistent levels of selection on the α1 and α2 domains. There were strong correlations in all selection measures (number of positively/negatively selected residues and dN/dS ratios) between both PBR exons. Similar positive associations were found for the level of amino acid polymorphism across the two domains. Conclusions We conclude that the strength of selection and the level of polymorphism are highly consistent between both peptide-binding domains (α1 and α2) of the avian MHC class I.

scholarly journals E2F1 binds to the peptide-binding groove within the BIR3 domain of cIAP1 and requires cIAP1 for chromatin binding

PLoS ONE ◽  
2018 ◽  
Vol 13 (10) ◽  
pp. e0206253 ◽  
Author(s):  
Jennifer Allègre ◽  
Jessy Cartier ◽  
Valérie Glorian ◽  
Nathalie Droin ◽  
Baptiste Dumetier ◽  
...  
Keyword(s):  
Peptide Binding ◽  
Chromatin Binding ◽  
Peptide Binding Groove ◽  
Binding Groove

scholarly journals Structures of the human Pals1 PDZ domain with and without ligand suggest gated access of Crb to the PDZ peptide-binding groove

2015 ◽  
Vol 71 (3) ◽  
pp. 555-564 ◽  
Author(s):  
Marina E. Ivanova ◽  
Georgina C. Fletcher ◽  
Nicola O'Reilly ◽  
Andrew G. Purkiss ◽  
Barry J. Thompson ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Interaction ◽  
Protein Complexes ◽  
Transmembrane Protein ◽  
Pdz Domain ◽  
Peptide Binding ◽  
Side Chain ◽  
Apical Plasma Membrane ◽  
Peptide Binding Groove ◽  
Binding Groove

Many components of epithelial polarity protein complexes possess PDZ domains that are required for protein interaction and recruitment to the apical plasma membrane. Apical localization of the Crumbs (Crb) transmembrane protein requires a PDZ-mediated interaction with Pals1 (protein-associated with Lin7, Stardust, MPP5), a member of the p55 family of membrane-associated guanylate kinases (MAGUKs). This study describes the molecular interaction between the Crb carboxy-terminal motif (ERLI), which is required forDrosophilacell polarity, and the Pals1 PDZ domain using crystallography and fluorescence polarization. Only the last four Crb residues contribute to Pals1 PDZ-domain binding affinity, with specificity contributed by conserved charged interactions. Comparison of the Crb-bound Pals1 PDZ structure with an apo Pals1 structure reveals a key Phe side chain that gates access to the PDZ peptide-binding groove. Removal of this side chain enhances the binding affinity by more than fivefold, suggesting that access of Crb to Pals1 may be regulated by intradomain contacts or by protein–protein interaction.

scholarly journals Diverse modes of binding in structures ofLeishmania majorN-myristoyltransferase with selective inhibitors

IUCrJ ◽  
2014 ◽  
Vol 1 (4) ◽  
pp. 250-260 ◽  
Author(s):  
James A. Brannigan ◽  
Shirley M. Roberts ◽  
Andrew S. Bell ◽  
Jennie A. Hutton ◽  
Michael R. Hodgkinson ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Active Sites ◽  
Screening Program ◽  
Peptide Binding ◽  
Effective Vaccine ◽  
Parasitic Infections ◽  
High Morbidity ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Myristoyl Coa

The leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed.N-Myristoyltransferase (NMT) has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT fromLeishmania donovanihave been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely relatedL. majorare reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic α-carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed.

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