scholarly journals Incorporating structural features to improve the prediction and understanding of pathogenic amino acid substitutions

10.52586/5036 ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 1422-1433
Author(s):  
Yao Xiong ◽  
Jing-Bo Zhou ◽  
Ke An ◽  
Wei Han ◽  
Tao Wang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Structural Features ◽  
Amino Acid Substitutions

scholarly journals Probing Structural Features of Alzheimer’s Amyloid-β Pores in Bilayers Using Site-Specific Amino Acid Substitutions

Biochemistry ◽  
2012 ◽  
Vol 51 (3) ◽  
pp. 776-785 ◽  
Author(s):  
Ricardo Capone ◽  
Hyunbum Jang ◽  
Samuel A. Kotler ◽  
Bruce L. Kagan ◽  
Ruth Nussinov ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amyloid Β ◽  
Structural Features ◽  
Amino Acid Substitutions ◽  
Site Specific ◽  
Specific Amino Acid

scholarly journals Triple arginines as molecular determinants for pentameric assembly of the intracellular domain of 5-HT3A receptors

2019 ◽  
Vol 151 (9) ◽  
pp. 1135-1145 ◽  
Author(s):  
Akash Pandhare ◽  
Elham Pirayesh ◽  
Antonia G. Stuebler ◽  
Michaela Jansen
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Amino Acid ◽  
Postoperative Nausea ◽  
Structural Features ◽  
Amino Acid Substitutions ◽  
Intracellular Domain ◽  
Molecular Determinants ◽  
Nausea And Emesis ◽  
Type 3

Serotonin type 3 receptors (5-HT3Rs) are cation-conducting pentameric ligand-gated ion channels and members of the Cys-loop superfamily in eukaryotes. 5-HT3Rs are found in the peripheral and central nervous system, and they are targets for drugs used to treat anxiety, drug dependence, and schizophrenia, as well as chemotherapy-induced and postoperative nausea and emesis. Decades of research of Cys-loop receptors have identified motifs in both the extracellular and transmembrane domains that mediate pentameric assembly. Those efforts have largely ignored the most diverse domain of these channels, the intracellular domain (ICD). Here we identify molecular determinants within the ICD of serotonin type 3A (5-HT3A) subunits for pentameric assembly by first identifying the segments contributing to pentamerization using deletion constructs of, and finally by making defined amino acid substitutions within, an isolated soluble ICD. Our work provides direct experimental evidence for the contribution of three intracellular arginines, previously implicated in governing the low conductance of 5-HT3ARs, in structural features such as pentameric assembly.

scholarly journals Triple Arginines as Molecular Determinants for Pentameric Assembly of the Intracellular Domain of 5-HT3A Receptors

2019 ◽  
Author(s):  
Akash Pandhare ◽  
Elham Pirayesh ◽  
Antonia G. Stuebler ◽  
Michaela Jansen
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Amino Acid ◽  
Drug Dependence ◽  
Structural Features ◽  
Amino Acid Substitutions ◽  
Intracellular Domain ◽  
Molecular Determinants ◽  
Nausea And Emesis ◽  
Post Operative Nausea

ABSTRACTSerotonin type 3A receptors (5-HT3ARs) are cation-conducting homo-pentameric ligand-gated ion channels (pLGICs) also known as the Cys-loop superfamily in eukaryotes. 5-HT3Rs are found in the peripheral and central nervous system, and they are targets for drugs used to treat anxiety, drug dependence, schizophrenia, as well as chemotherapy-induced and post-operative nausea and emesis. Decades of research of Cys-loop receptors have identified motifs in both the extracellular and transmembrane domains that mediate pentameric assembly. Those efforts have largely ignored the most diverse domain of these channels, the intracellular domain (ICD). Here we identify molecular determinants inside the ICD for pentameric assembly by first identifying the segments contributing to pentamerization using deletion constructs, and remarkably by making a small number of defined amino acid substitutions. Our work provides direct experimental evidence for the contribution of three arginines, previously implicated in governing the low conductance of 5-HT3ARs, in structural features such as pentameric assembly.

Recombinant Variants of Tissue-Type Plasminogen Activator Containing Amino Acid Substitutions in the Finger Domain

1992 ◽  
Vol 68 (06) ◽  
pp. 672-677 ◽  
Author(s):  
Hitoshi Yahara ◽  
Keiji Matsumoto ◽  
Hiroyuki Maruyama ◽  
Tetsuya Nagaoka ◽  
Yasuhiro Ikenaka ◽  
...  
Keyword(s):  
Amino Acid ◽  
Plasminogen Activator ◽  
Half Life ◽  
Tissue Type ◽  
Clot Lysis ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Plasma Clot ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryTissue-type plasminogen activator (t-PA) is a fibrin-specific agent which has been used to treat acute myocardial infarction. In an attempt to clarify the determinants for its rapid clearance in vivo and high affinity for fibrin clots, we produced five variants containing amino acid substitutions in the finger domain, at amino acid residues 7–9, 10–14, 15–19, 28–33, and 37–42. All the variants had a prolonged half-life and a decreased affinity for fibrin of various degrees. The 37–42 variant demonstrated about a 6-fold longer half-life with a lower affinity for fibrin. Human plasma clot lysis assay estimated the fibrinolytic activity of the 37–42 variant to be 1.4-fold less effective than that of the wild-type rt-PA. In a rabbit jugular vein clot lysis model, doses of 1.0 and 0.15 mg/kg were required for about 70% lysis in the wild-type and 37–42 variant, respectively. Fibrinogen was degraded only when the wild-type rt-PA was administered at a dose of 1.0 mg/kg. These findings suggest that the 37–42 variant can be employed at a lower dosage and that it is a more fibrin-specific thrombolytic agent than the wild-type rt-PA.

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