scholarly journals Changes in the repertoire of peptides bound to HLA-B27 subtypes and to site-specific mutants inside and outside pocket B.

1993 ◽  
Vol 177 (3) ◽  
pp. 613-620 ◽  
Author(s):  
S Rojo ◽  
F García ◽  
J A Villadangos ◽  
J A López de Castro
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Peptide Binding ◽  
Peptide Pool ◽  
Structural Features ◽  
Metabolic Labeling ◽  
Hla B27 ◽  
Peptide Binding Site ◽  
Network Of Hydrogen Bonds ◽  
Degree Of Similarity ◽  
Do So

HLA-B27 subtypes share many structural features, including their pocket B, which interacts with a conserved Arg residue at the second position of B*2705-bound peptides. Subtypes differ among each other at other locations in the peptide binding site. In this study, metabolic labeling and radiochemical pool sequencing were used to address the following issues: (a) presence of the Arg 2 (R2) motif among peptides bound to the various HLA-B27 subtypes; (b) influence of mutations inside and outside pocket B on this motif; and (c) the degree of similarity among the peptide pools bound to the various B27 subtypes. Sequencing of Arg-labeled peptide pools extracted from B*2701 to B*2706, and from two site-directed mutants of B*2705 with changes outside pocket B, indicated that all of these molecules bind peptides with Arg at position 2. Peptides from several mutants with changes altering the structure of pocket B, and from one mutant at the pocket B rim, also retained the R2 motif. However, this was absent in the peptide pool extracted from the M45 mutant, in which the negative charge of pocket B, conferred to HLA-B27 by Glu45, was canceled. These results indicate that alterations outside pocket B, and even disruption of the network of hydrogen bonds that stabilizes Arg binding in pocket B, do not impair binding of peptides bearing the R2 motif, but a nonconservative substitution at position 45 does. As a substantial fraction of anti-B*2705 cytotoxic T lymphocyte (CTL) clones crossreact with the M45 mutant (Villadangos, J., B. Galocha, D. López, V. Calvo, and J. A. López de Castro. 1992. J. Immunol. 149:505) this result suggest that determinant mimicry by nonidentical peptides may frequently account for unexpected CTL crossreactions. Metabolic labeling with various other amino acids and radiochemical sequencing revealed similarities, but also substantial differences, among the peptide pools from the various HLA-B27 subtypes. This strongly suggests that many peptides bind to multiple subtypes, but significant subsets of peptides bound to a given HLA-B27 subtype do not bind to other subtypes or do so with greatly altered efficiency. These results indicate the importance of polymorphism outside pocket B in modulating peptide binding to HLA-B27.

scholarly journals Different HLA-B27 subtypes present the same immunodominant Epstein-Barr virus peptide.

1993 ◽  
Vol 178 (3) ◽  
pp. 879-887 ◽  
Author(s):  
J M Brooks ◽  
R J Murray ◽  
W A Thomas ◽  
M G Kurilla ◽  
A B Rickinson
Keyword(s):  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Strong Association ◽  
Peptide Binding ◽  
Nuclear Antigen ◽  
Peptide Motif ◽  
Hla B27 ◽  
Barr Virus ◽  
Epstein Barr ◽  
Ctl Responses

An immunological basis has been postulated for the strong association between at least five subtypes of the HLA-B27 allele (B27.01, .02, .04, .05, and .06) and ankylosing spondylitis, namely that cytotoxic T lymphocyte (CTL) responses are induced against an "arthritogenic" peptide that these different subtypes can all present. This requires a degree of overlap between the peptide binding repertoires of different B27 molecules. The present work, using CTL responses to Epstein-Barr virus (EBV) as a model system in which to identify B27-restricted epitopes, provides the first direct evidence that different disease-related alleles can present the same immunodominant peptide. We first noted that EBV-specific CTL clones, whether from B27.05-, B27.02-, or B27.04-positive donors, were largely subtype-specific in their restriction, recognizing only EBV-transformed B cell lines of the relevant B27 subtype. However, when tested against targets expressing individual EBV proteins from recombinant vaccinia virus vectors, all B27.05-restricted, all B27.02-restricted, and a proportion of B27.04-restricted clones were reactive to the same viral nuclear antigen, Epstein-Barr nuclear antigen (EBNA)3C. In subsequent peptide sensitization assays, all the EBNA3C-specific clones tested and also the EBNA3C-specific component within polyclonal CTL preparations from B27.05-, B27.02-, or B27.04-positive donors recognized the same immunodominant viral peptide RRIYDLIEL (EBNA3C residues 258-266). This sequence accords well with the proposed B27.05 peptide motif and clearly must be accommodated within the different peptide binding grooves of B27.05, B27.02, and B27.04 molecules. Clonal analysis revealed a second component of the B27.04-restricted response that was not shared with other subtypes. This was directed against an EBV latent membrane protein LMP2 epitope whose sequence RRRWRRLTV satisfies some but not all requirements of the B27.05 peptide motif. We conclude that there is indeed a degree of functional overlap between different B27 subtypes in their selection and presentation of CTL epitopes.

Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

2020 ◽  
Author(s):  
Luke Adams ◽  
Lorna E. Wilkinson-White ◽  
Menachem J. Gunzburg ◽  
Stephen J. Headey ◽  
Martin J. Scanlon ◽  
...  
Keyword(s):  
Binding Site ◽  
Systematic Approach ◽  
Structural Information ◽  
Peptide Binding ◽  
Chemical Diversity ◽  
Chemical Probes ◽  
Protein Targets ◽  
Structure Activity ◽  
Peptide Binding Site ◽  
Selection Of

The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.<br>

Allotopic antagonism of the non-peptide atrial natriuretic peptide (ANP) antagonist HS-142-1 on natriuretic peptide receptor NPR-A

2002 ◽  
Vol 362 (2) ◽  
pp. 231-237 ◽  
Author(s):  
Hugo POIRIER ◽  
Jean LABRECQUE ◽  
Julie DESCHÊNES ◽  
André DeLÉAN
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Mode Of Action ◽  
Transmembrane Domain ◽  
Peptide Binding ◽  
Natriuretic Peptide Receptor ◽  
Receptor Dimerization ◽  
Peptide Receptor ◽  
Peptide Binding Site ◽  
Atrial Natriuretic

The microbial polysaccharide HS-142-1 has been documented as an antagonist of natriuretic peptides. It inhibits activation and peptide binding to both guanylate receptors natriuretic peptide receptor (NPR)-A and NPR-B, but has no effect on the non-cyclase receptor NPR-C. At first sight the effect of HS-142-1 on peptide binding appears to be surmountable, suggesting that it might be competitive despite its chemically divergent nature. We explored its mode of action on wild-type NPR-A (WT), on a disulphide-bridged constitutively active mutant (C423S) and on truncated mutants lacking either their cytoplasmic domain (ΔKC) or both the cytoplasmic and the transmembrane domains (ECD). On the WT, HS-142-1 inhibited atrial natriuretic peptide (ANP) binding with a pK value of 6.51±0.07 (Kd = 0.31μM). It displayed a similar effect on the C423S mutant (pK = 6.31±0.11), indicating that its action might not be due to interference with receptor dimerization. HS-142-1 also inhibited ANP binding to ΔKC with a pK of 7.05±0.05 (Kd = 0.089μM), but it was inactive on ANP binding to ECD at a concentration of 10−4M, suggesting that the antagonism was not competitive at the peptide-binding site located on the ECD and that the transmembrane domain might be required. HS-142-1 also enhanced dissociation of NPR-A-bound 125I-ANP in the presence of excess unlabelled ANP, implying an allotopic (allosteric) mode of action for the antagonist.

Solubilization and Characterization of Calcitonin Gene-Related Peptide Binding Site from Porcine Spinal Cord

1988 ◽  
Vol 50 (2) ◽  
pp. 480-485 ◽  
Author(s):  
Osamu Hiroshima ◽  
Yoshihisa Sano ◽  
Teruaki Yuzuriha ◽  
Chiyuki Yamato ◽  
Akira Saito ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Binding Site ◽  
Peptide Binding ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Peptide Binding Site

The Crystal Structures of the SH2 Domain of p56lckComplexed with Two Phosphonopeptides Suggest a Gated Peptide Binding Site

1995 ◽  
Vol 246 (2) ◽  
pp. 344-355 ◽  
Author(s):  
Vincent Mikol ◽  
Götz Baumann ◽  
Thomas H. Keller ◽  
Ute Manning ◽  
Mauro G.M. Zurini
Keyword(s):  
Binding Site ◽  
Crystal Structures ◽  
Peptide Binding ◽  
Sh2 Domain ◽  
Peptide Binding Site

scholarly journals IX. On the structure and development of the liver

1849 ◽  
Vol 139 ◽  
pp. 109-137 ◽  
Keyword(s):  
Royal Society ◽  
A Priori ◽  
Structural Features ◽  
Structure And Function ◽  
Conclusive Evidence ◽  
Interesting Paper ◽  
Biliary Ducts ◽  
And Function ◽  
Do So

In venturing to offer a second communication to the Royal Society respecting the structure of the liver, I feel the rather anxious to do so, that I may have an opportunity of correcting an error and supplying a deficiency which existed in my previous paper. In the following observations I purpose to present some account of the structure of the liver examined in the ascending series of animals, and also to describe the several stages of its evolution in the embryo; in this way I trust I may be able to exhibit the characteristic structural features of the organ as it exists in Man and the higher animals, and also to determine the true place which ought to be assigned to it in a classification of the various glandular organs occurring in the same. I am not aware that any detailed account of the structure of the liver has been recently published, except that by M. Natalis Guillot, which however, so far as I comprehend it, does not seem to be one that can be readily accepted; the idea that the minute biliary ducts and lymphatics originate together in a common net-work, is à priori improbable, and entirely opposed to conclusive evidence (as I think), which will be subsequently adduced. A very interesting paper on the structure and function of the liver has also appeared in the 4th volume of the Guy’s Hospital Reports, from the pen of Dr. Williams; to his labours I shall several times have occasion to refer, but it will be seen that I differ from him in several particulars, especially respecting the importance of the basement or limitary membrane.

scholarly journals Peptide-binding motifs associated with MHC molecules common in Chinese rhesus macaques are analogous to those of human HLA supertypes and include HLA-B27-like alleles

2013 ◽  
Vol 65 (5) ◽  
pp. 371-386 ◽  
Author(s):  
Bianca R. Mothé ◽  
Scott Southwood ◽  
John Sidney ◽  
A. Michelle English ◽  
Amanda Wriston ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Peptide Binding ◽  
Hla B27 ◽  
Binding Motifs ◽  
Mhc Molecules ◽  
Chinese Rhesus Macaques
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