HUMA: A platform for the analysis of genetic variation in humans

Brown, David K.; Bishop, Özlem Tastan

doi:10.1002/humu.23334

Cited by 9 publications

(11 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data retrieval from the Ensembl [43] and HUMA [44] databases identified six validated SNVs with pathogenic effects (Table 1). Even though there were several more SNVs, we limited our CA-II dataset to those validated within dbSNP via frequency, or via cluster, and containing a phenotype annotation.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

2019

View full text Add to dashboard Cite

Human carbonic anhydrase II (CA-II) is a Zinc (Zn2+) metalloenzyme responsible for maintenance of acid-base balance within the body through the reversible hydration of CO2 to produce protons (H+) and bicarbonate (BCT). Due to its importance, alterations to the amino acid sequence of the protein as a result of single nucleotide variations (nsSNVs) have detrimental effects on homeostasis. Six pathogenic CA-II nsSNVs, K18E, K18Q, H107Y, P236H, P236R and N252D were identified, and variant protein models calculated using homology modeling. The effect of each nsSNV was analyzed using motif analysis, molecular dynamics (MD) simulations, principal component (PCA) and dynamic residue network (DRN) analysis. Motif analysis identified 11 functionally important motifs in CA-II. RMSD data indicated subtle SNV effects, while PCA analysis revealed that the presence of BCT results in greater conformational sampling and free energy in proteins. DRN analysis showed variant allosteric effects, and the average betweenness centrality (BC) calculations identified Glu117 as the most important residue for communication in CA-II. The presence of BCT was associated with a reduction to Glu117 usage in all variants, suggesting implications for Zn2+ dissociation from the CA-II active site. In addition, reductions to Glu117 usage are associated with increases in the usage of the primary and secondary Zn2+ ligands; His94, His96, His119 and Asn243 highlighting potential compensatory mechanisms to maintain Zn2+ within the active site. Compared to traditional MD simulation investigation, DRN analysis provided greater insights into SNV mechanism of action, indicating its importance for the study of missense mutation effects in proteins and, in broader terms, precision medicine related research.

show abstract

Section: Resultsmentioning

confidence: 99%

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

2019

View full text Add to dashboard Cite

show abstract

“…This opens the door to personalized medicine, where knowledge of drug-resistant and drug-sensitive SNPs can assist in the development of effective biomarkers [99] and allow treatments to be tailored to individual patients [102,103]. Furthermore, understanding structural changes caused by nsSNPs would enable the design of novel drugs to target these mutations and, thus, is key in advancing precision/personalized medicine [104,105]. One example can be given from stroke and stroke-related medications.…”

Section: Understanding the Allosteric Effects Of Disease And Drug-resmentioning

confidence: 99%

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

Amamuddy

Veldman

Manyumwa

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. As such, the critical analysis and integration of established approaches into robust, reproducible, and customizable computational pipelines with experimental feedback could make allosteric drug discovery more efficient and reliable. In this article, we review computational approaches for allosteric drug discovery and discuss how these tools can be utilized to develop consensus workflows for in silico identification of allosteric sites and modulators with some applications to pathogen resistance and precision medicine. The emerging realization that allosteric modulators can exploit distinct regulatory mechanisms and can provide access to targeted modulation of protein activities could open opportunities for probing biological processes and in silico design of drug combinations with improved therapeutic indices and a broad range of activities.

show abstract

“…The Ensembl [34] and Human Mutation Analysis (HUMA) [35] databases identified three pathogenic nsSNVs and two benign SNV (see Table 1). An additional variant G162R was identified from literature studies [32].…”

Section: Data Retrieval Identifies Snvs Pathogenic To Ca-viiimentioning

confidence: 99%

“…These variations have the same rs ID and demonstrate that at position 100, Ser can either be mutated to an Ala or a Pro residue. Of the six identified SNVs, VAPOR (Variant Analysis Portal) [35] (Table 1) shows that I-Mutant [36] and MUpro [37] predicted stability reduction in all. With respect to the clinical significance of the variants, S100L and E109D are regarded as benign.…”

Section: Data Retrieval Identifies Snvs Pathogenic To Ca-viiimentioning

confidence: 99%

See 1 more Smart Citation

Structural Characterization of Carbonic Anhydrase VIII and Effects of Missense Single Nucleotide Variations to Protein Structure and Function

Sanyanga

Bishop

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Human carbonic anhydrase 8 (CA-VIII) is an acatalytic isoform of the α -CA family. Though the protein cannot hydrate CO2, CA-VIII is essential for calcium (Ca2+) homeostasis within the body, and achieves this by allosterically inhibiting the binding of inositol 1,4,5-triphosphate (IP3) to the IP3 receptor type 1 (ITPR1) protein. However, the mechanism of interaction of CA-VIII to ITPR1 is not well understood. In addition, functional defects to CA-VIII due to non-synonymous single nucleotide polymorphisms (nsSNVs) result in Ca2+ dysregulation and the development of the phenotypes such as cerebellar ataxia, mental retardation and disequilibrium syndrome 3 (CAMRQ3). The pathogenesis of CAMRQ3 is also not well understood. The structure and function of CA-VIII was characterised, and pathogenesis of CAMRQ3 investigated. Structural and functional characterisation of CA-VIII was conducted through SiteMap and CPORT to identify potential binding site residues. The effects of four pathogenic nsSNVs, S100A, S100P, G162R and R237Q, and two benign S100L and E109D variants on CA-VIII structure and function was then investigated using molecular dynamics (MD) simulations, dynamic cross correlation (DCC) and dynamic residue network (DRN) analysis. SiteMap and CPORT analyses identified 38 unique CA-VIII residues that could potentially bind to ITPR1. MD analysis revealed less conformational sampling within the variant proteins and highlighted potential increases to variant protein rigidity. Dynamic cross correlation (DCC) showed that wild-type (WT) protein residue motion is predominately anti-correlated, with variant proteins showing no correlation to greater residue correlation. DRN revealed variant-associated increases to the accessibility of the N-terminal binding site residues, which could have implications for associations with ITPR1, and further highlighted differences to the mechanism of benign and pathogenic variants. SNV presence is associated with a reduction to the usage of Trp37 in all variants, which has implications for CA-VIII stability. The differences to variant mechanisms can be further investigated to understand pathogenesis of CAMRQ3, enhancing precision medicine-related studies into CA-VIII.

show abstract

HUMA: A platform for the analysis of genetic variation in humans

Abstract: The completion of the human genome project at the beginning of the 21st century, along with the

Cited by 9 publications

References 36 publications

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

Structural Characterization of Carbonic Anhydrase VIII and Effects of Missense Single Nucleotide Variations to Protein Structure and Function

Contact Info

Product

Resources

About