scholarly journals Crystal structures of Hsp104 N-terminal domains fromSaccharomyces cerevisiaeandCandida albicanssuggest the mechanism for the function of Hsp104 in dissolving prions

2017 ◽  
Vol 73 (4) ◽  
pp. 365-372 ◽  
Author(s):  
Peng Wang ◽  
Jingzhi Li ◽  
Clarissa Weaver ◽  
Aaron Lucius ◽  
Bingdong Sha
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
High Resolution ◽  
Crystal Structures ◽  
Molecular Chaperone ◽  
Peptide Binding ◽  
Dimer Formation ◽  
Peptide Substrates ◽  
Peptide Binding Groove ◽  
Binding Groove

Hsp104 is a yeast member of the Hsp100 family which functions as a molecular chaperone to disaggregate misfolded polypeptides. To understand the mechanism by which the Hsp104 N-terminal domain (NTD) interacts with its peptide substrates, crystal structures of the Hsp104 NTDs fromSaccharomyces cerevisiae(ScHsp104NTD) andCandida albicans(CaHsp104NTD) have been determined at high resolution. The structures of ScHsp104NTD and CaHsp104NTD reveal that the yeast Hsp104 NTD may utilize a conserved putative peptide-binding groove to interact with misfolded polypeptides. In the crystal structures ScHsp104NTD forms a homodimer, while CaHsp104NTD exists as a monomer. The consecutive residues Gln105, Gln106 and Lys107, and Lys141 around the putative peptide-binding groove mediate the monomer–monomer interactions within the ScHsp104NTD homodimer. Dimer formation by ScHsp104NTD suggests that the Hsp104 NTD may specifically interact with polyQ regions of prion-prone proteins. The data may reveal the mechanism by which Hsp104 NTD functions to suppress and/or dissolve prions.

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 High-resolution crystal structures of alternate forms of the human CD44 hyaluronan-binding domain reveal a site for protein interaction

2014 ◽  
Vol 70 (9) ◽  
pp. 1155-1161 ◽  
Author(s):  
Li-Kai Liu ◽  
Barry Finzel
Keyword(s):  
High Resolution ◽  
Crystal Structures ◽  
Crystal Form ◽  
Binding Domain ◽  
Structural Deformation ◽  
Monoclinic Form ◽  
Alternate Forms ◽  
Binding Groove ◽  
A Site ◽  
Hyaluronan Binding

Two new crystal structures of the extracellular hyaluronan-binding domain of human CD44 are described at high resolution. A hexagonal crystal form at 1.60 Å resolution and a monoclinic form at 1.08 Å resolution both have two molecules in the asymmetric unit arranged about a similar noncrystallographic twofold axis of symmetry. These structures are compared with those previously reported at 2.20 Å resolution to show that the fold is quite resistant to structural deformation in different crystal environments. Unexpectedly, a short peptide is found in the monoclinic crystals at a site remote from the known hyaluronan-binding groove. The peptide with a valine at the carboxy-terminus must have co-purified from the bacterial expression host and binds on the opposite side of the domain from the known hyaluronan-binding groove. This opportunistic binding may identify a site of interaction used as CD44 assembles with other proteins to accomplish effective signaling regarding changes to the extracellular environment.

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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