scholarly journals Single Amino Acid Substitution in the Vicinity of a Receptor-Binding Domain Changes Protein–Peptide Binding Affinity

ACS Omega ◽  
2017 ◽  
Vol 2 (9) ◽  
pp. 5445-5452 ◽  
Author(s):  
Galina Malovichko ◽  
Xiangdong Zhu
Keyword(s):  
Amino Acid ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Amino Acid Substitution ◽  
Peptide Binding ◽  
Binding Domain ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Peptide Binding Affinity

Single amino acid substitution (840Arg → His) in the hormone-binding domain of the androgen receptor leads to incomplete androgen insensitivity syndrome associated with a thermolabile androgen receptor

1994 ◽  
Vol 130 (6) ◽  
pp. 569-574 ◽  
Author(s):  
Kyosuke Imasaki ◽  
Tomonobu Hasegawa ◽  
Taijiro Okabe ◽  
Yoshiyuki Sakai ◽  
Masafumi Haji ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Amino Acid ◽  
Amino Acid Substitution ◽  
Androgen Insensitivity Syndrome ◽  
Binding Domain ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
Hormone Binding ◽  
Androgen Insensitivity ◽  
Hormone Binding Domain

Imasaki K, Hasegawa T. Okabe T. Sakai Y. Haji M. Takayanagi R, Nawata H. Single amino acid substitution (840Arg → His) in the hormone-binding domain of the androgen receptor leads to incomplete androgen insensitivity syndrome associated with a thermolabile androgen receptor. Eur I Endocrinol 1994;130:569–74. ISSN 0804–4643 We have characterized the androgen receptor in a Japanese girl and her maternal cousin in a family with incomplete androgen insensitivity syndrome, and have investigated the molecular basis. Wholecell androgen binding assay in cultured genital skin fibroblasts from both patients showed a normal maximum binding capacity and a normal apparent dissociation constant. However, androgen binding in fibroblasts from both patients decreased to 30% when the assay temperature was raised from 30°C to 41°C, indicating the presence of the thermolability of ligand binding to the androgen receptor. Sequence analysis of the coding exons of the androgen receptor gene from the patients revealed a single nucleotide substitution at position 2881 in exon G, resulting in the conversion of arginine (CGT) to histidine (CAT) at amino acid position 840 in the hormone-binding domain of the androgen receptor. The family study showed that the mothers and the maternal grandmother of the patients are heterozygous carriers for this mutation, whereas the father does not carry it, supporting the view that androgen insensitivity syndrome is an X chromosome-linked disorder. The single amino acid substitution may explain the qualitative abnormality of the androgen receptor displaying thermolability, which is thought to be the pathogenesis of incomplete androgen insensitivity syndrome in the patients. Kyosuke Imasaki, Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan

scholarly journals Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016

2021 ◽  
Author(s):  
Tyler N. Starr ◽  
Allison J. Greaney ◽  
Adam S. Dingens ◽  
Jesse D. Bloom
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Amino Acid ◽  
Receptor Binding ◽  
Binding Domain ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Antigenic Evolution

AbstractMonoclonal antibodies and antibody cocktails are a promising therapeutic and prophylaxis for COVID-19. However, ongoing evolution of SARS-CoV-2 can render monoclonal antibodies ineffective. Here we completely map all mutations to the SARS-CoV-2 spike receptor binding domain (RBD) that escape binding by a leading monoclonal antibody, LY-CoV555, and its cocktail combination with LY-CoV016. Individual mutations that escape binding by each antibody are combined in the circulating B.1.351 and P.1 SARS-CoV-2 lineages (E484K escapes LY-CoV555, K417N/T escape LY-CoV016). Additionally, the L452R mutation in the B.1.429 lineage escapes LY-CoV555. Furthermore, we identify single amino acid changes that escape the combined LY-CoV555+LY-CoV016 cocktail. We suggest that future efforts should diversify the epitopes targeted by antibodies and antibody cocktails to make them more resilient to antigenic evolution of SARS-CoV-2.

scholarly journals Murine Coronavirus Evolution In Vivo: Functional Compensation of a Detrimental Amino Acid Substitution in the Receptor Binding Domain of the Spike Glycoprotein

2005 ◽  
Vol 79 (12) ◽  
pp. 7629-7640 ◽  
Author(s):  
Sonia Navas-Martin ◽  
Susan T. Hingley ◽  
Susan R. Weiss
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Receptor Binding ◽  
Amino Acid Substitution ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Functional Compensation

ABSTRACT Murine coronavirus A59 strain causes mild to moderate hepatitis in mice. We have previously shown that mutants of A59, unable to induce hepatitis, may be selected by persistent infection of primary glial cells in vitro. These in vitro isolated mutants encoded two amino acids substitutions in the spike (S) gene: Q159L lies in the putative receptor binding domain of S, and H716D, within the cleavage signal of S. Here, we show that hepatotropic revertant variants may be selected from these in vitro isolated mutants (Q159L-H716D) by multiple passages in the mouse liver. One of these mutants, hr2, was chosen for more in-depth study based on a more hepatovirulent phenotype. The S gene of hr2 (Q159L- R654H -H716D- E1035D ) differed from the in vitro isolates (Q159L-H716D) in only 2 amino acids (R654H and E1035D). Using targeted RNA recombination, we have constructed isogenic recombinant MHV-A59 viruses differing only in these specific amino acids in S (Q159L-R654H-H716D-E1035D). We demonstrate that specific amino acid substitutions within the spike gene of the hr2 isolate determine the ability of the virus to cause lethal hepatitis and replicate to significantly higher titers in the liver compared to wild-type A59. Our results provide compelling evidence of the ability of coronaviruses to rapidly evolve in vivo to highly virulent phenotypes by functional compensation of a detrimental amino acid substitution in the receptor binding domain of the spike glycoprotein.

scholarly journals Envelope Proteins Containing Single Amino Acid Substitutions Support a Structural Model of the Receptor-Binding Domain of Bovine Leukemia Virus Surface Protein

2002 ◽  
Vol 76 (21) ◽  
pp. 10861-10872 ◽  
Author(s):  
Elizabeth R. Johnston ◽  
Lorraine M. Albritton ◽  
Kathryn Radke
Keyword(s):  
Amino Acid ◽  
Receptor Binding ◽  
Bovine Leukemia Virus ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Binding Domain ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Env Protein ◽  
Murine Leukemia

ABSTRACT Functional domains of the strikingly conserved envelope (Env) glycoproteins of bovine leukemia virus (BLV) and its close relative, human T-cell leukemia virus type 1 (HTLV-1), are still being defined. We have used BLV Env protein variants to gain insights into the structure and function of this important determinant of viral infectivity. Each of 23 different single amino acid variants found in cDNA clones of env transcripts present after short-term culture of peripheral blood mononuclear cells from BLV-infected sheep was expressed in COS-1 cells and tested for the ability to mediate cell fusion and to be cleaved to surface (SU) and transmembrane (TM) protein subunits. Of 11 Env variants that failed to induce syncytia or did so poorly, 7 contained changes in amino acids identical or chemically conserved in the HTLV-1 Env protein. These seven included the four variants that showed aberrant proteolytic cleavage and poor cell surface expression, underscoring their importance for Env structure. Ten of 12 variants that retained wild-type syncytium-inducing ability clustered in the N-terminal half of BLV SU, which forms the putative receptor-binding domain (RBD). Several variants in the RBD showed evidence of subtle misfolding, as judged by reduced binding to monoclonal antibodies recognizing conformational epitopes F, G, and H formed by the N terminus of SU. We modeled the BLV RBD by aligning putative structural elements with known elements of the ecotropic Friend murine leukemia virus RBD monomer. All the variant RBD residues but one are exposed on the surface of this BLV model. These variants as well as function-altering, antibody-reactive residues defined by other investigators group on one face of the molecular model. They are strikingly absent from the opposite face, implying that it is likely to face inward in Env complexes. This surface might interact with the C-terminal domain of SU or with an adjacent monomer in the Env oligomer. This location suggests an orientation for the monomer of ecotropic Friend murine leukemia virus RBD.

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