Molecular Basis for Resistance of Acanthamoeba Tubulins to All Major Classes of Antitubulin Compounds

Despite the ubiquity of stacking interactions between heterocycles and aromatic amino acids in biological systems, our ability to predict their strength, even qualitatively, is limited. Based on rigorous ab initio data, we have devised a simple predictive model of the strength of stacking interactions between heterocycles commonly found in biologically active molecules and the amino acid side chains Phe, Tyr, and Trp. This model provides rapid predictions of the stacking ability of a given heterocycle based on readily-computed heterocycle descriptors. We show that the values of these descriptors, and therefore the strength of stacking interactions with aromatic amino acid side chains, follow simple predictable trends and can be modulated by changing the number and distribution of heteroatoms within the heterocycle. This provides a simple conceptual model for understanding stacking interactions in protein binding sites and optimizing inhibitor binding in drug design.

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Predicting the Strength of Stacking Interactions Between Heterocycles and Aromatic Amino Acid Side Chains

10.26434/chemrxiv.7628939.v3 ◽

2019 ◽

Author(s):

Andrea N. Bootsma ◽

Analise C. Doney ◽

Steven Wheeler

Keyword(s):

Amino Acid ◽

Binding Sites ◽

Aromatic Amino Acid ◽

Aromatic Amino Acids ◽

Biologically Active ◽

Side Chains ◽

Stacking Interactions ◽

Inhibitor Binding ◽

Protein Binding Sites ◽

Amino Acid Side Chains

Despite the ubiquity of stacking interactions between heterocycles and aromatic amino acids in biological systems, our ability to predict their strength, even qualitatively, is limited. Based on rigorous ab initio data, we have devised a simple predictive model of the strength of stacking interactions between heterocycles commonly found in biologically active molecules and the amino acid side chains Phe, Tyr, and Trp. This model provides rapid predictions of the stacking ability of a given heterocycle based on readily-computed heterocycle descriptors. We show that the values of these descriptors, and therefore the strength of stacking interactions with aromatic amino acid side chains, follow simple predictable trends and can be modulated by changing the number and distribution of heteroatoms within the heterocycle. This provides a simple conceptual model for understanding stacking interactions in protein binding sites and optimizing inhibitor binding in drug design.

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Molecular basis of N-acetylglucosaminyltransferase I deficiency in Arabidopsis thaliana plants lacking complex N-glycans

Biochemical Journal ◽

10.1042/bj20041686 ◽

2005 ◽

Vol 387 (2) ◽

pp. 385-391 ◽

Cited By ~ 56

Author(s):

Richard STRASSER ◽

Johannes STADLMANN ◽

Barbara SVOBODA ◽

Friedrich ALTMANN ◽

Josef GLÖSSL ◽

...

Keyword(s):

Arabidopsis Thaliana ◽

Amino Acid ◽

Heterologous Expression ◽

Molecular Cloning ◽

Molecular Basis ◽

Insect Cells ◽

Glycosylation Site ◽

Enzymic Activity ◽

Critical Amino Acid ◽

High Mannose

GnTI (N-acetylglucosaminyltransferase I) is a Golgi-resident enzyme essential for the processing of high-mannose to hybrid and complex N-glycans. The Arabidopsis thaliana cgl mutant lacks GnTI activity and as a consequence accumulates oligomannosidic structures. Molecular cloning of cgl GnTI cDNA revealed a point mutation, which causes a critical amino acid substitution (Asp144→Asn), thereby creating an additional N-glycosylation site. Heterologous expression of cgl GnTI in insect cells confirmed its lack of activity and the use of the N-glycosylation site. Remarkably, introduction of the Asp144→Asn mutation into rabbit GnTI, which does not result in the formation of a new N-glycosylation site, led to a protein with strongly reduced, but still detectable enzymic activity. Expression of Asn144 rabbit GnTI in cgl plants could partially restore complex N-glycan formation. These results indicate that the complete deficiency of GnTI activity in cgl plants is mainly due to the additional N-glycan, which appears to interfere with the proper folding of the enzyme.

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Amino Acid Substitutions in Transmembrane Domains 9 and 10 of GerVB That Affect the Germination Properties of Bacillus megaterium Spores

Journal of Bacteriology ◽

10.1128/jb.01073-08 ◽

2008 ◽

Vol 190 (24) ◽

pp. 8009-8017 ◽

Cited By ~ 14

Author(s):

Graham Christie ◽

Christopher R. Lowe

Keyword(s):

Amino Acid ◽

Bacillus Megaterium ◽

Binding Sites ◽

Molecular Basis ◽

Transmembrane Domains ◽

Site Directed Mutagenesis ◽

Amino Acid Substitutions ◽

Receptor Function ◽

Outer Loop ◽

Receptor Proteins

ABSTRACT The molecular basis for differences in germinant recognition of Bacillus megaterium QM B1551 spores containing the GerVB and/or GerUB receptor proteins has been examined by site-directed mutagenesis and the construction of cross-homologue chimeras. Focusing on nonconserved residues predicted to reside in transmembrane domains 9 and 10, we demonstrate that GerVB residues Ser319 and Leu345 are of particular importance in defining the specificity and apparent affinity of the receptor for germinants. Kinetic analyses of mutants with different amino acid substitutions at these positions indicate that Ser319 and Leu345 are not involved directly in the binding of germinants, but probably reside in regions of the receptor where structural perturbations can affect the conformation of, or access to, germinant binding sites. Position 345 is also shown to be of importance in GerUB, where the F345A mutation severely impairs receptor function. Functionality is restored in the GerUB Ala345 background by substituting putative outer-loop residues adjacent to TM10 for the corresponding residues in GerVB, indicating that a degree of structural coordination between these regions is important to receptor function.

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Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200303130833 ◽

2020 ◽

Vol 20 (11) ◽

pp. 1017-1030

Author(s):

Haonan Zhang ◽

Zhengquan Gao ◽

Chunxiao Meng ◽

Xiangqian Li ◽

Dayong Shi

Keyword(s):

Small Molecule ◽

Protein Tyrosine Phosphatase ◽

Binding Sites ◽

Drug Target ◽

Tyrosine Phosphatase ◽

Cancer Drug ◽

Cellular Activity ◽

Binding Modes ◽

Inhibitor Binding ◽

Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

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A Modified Autonomous En Transposon in Maize (Zea mays L.) Elicits a Differential Response of Reporter Alleles

Genetics ◽

10.1093/genetics/147.3.1329 ◽

1997 ◽

Vol 147 (3) ◽

pp. 1329-1338

Author(s):

Peter A Peterson

Keyword(s):

Molecular Structure ◽

Binding Sites ◽

Molecular Basis ◽

Zea Mays L ◽

Phenotypic Expression ◽

Terminal Inverted Repeat ◽

Coding Sequences ◽

Defective Element ◽

Related Element ◽

Unstable Genes

Transposable elements in maize are composed of a defined molecular structure that includes coding sequences, determiners of functionality and ordered terminal motifs that provide binding sites for transposase proteins. Alterations in these components change the phenotypic expression of unstable genes with transposon inserts. The molecular basis for the altered timing and frequency of transposition as determined by the size and number of spots on kernels or stripes on leaves has generally been described for defective inserts in genes. Most differential patterns can be ascribed to alterations in the terminal motifs of the reporter allele structure that supplies a substrate (terminal inverted repeat motifs) for transposase activity. For autonomously functioning alleles, the explanations for changes in phenotype are not so clear. In this report, an En-related element identified as F-En is described that shares with En the recognition of a specific defective element c1(mr)888104 but differs from En in that this F-En element does not recognize the canonical c1(mr) elements that are recognized by En. Evidence is provided suggesting that F-En does not recognize other En/Spm-related defective elements, some of whose sequences are known. This modified En arose from a c1-m autonomously mutating En allele.

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