Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding

• Published in: International journal of molecular sciences Vol. 20; no. 24; p. 6256
• Main Authors: Dash, Raju, Ali, Md Chayan, Dash, Nayan, Azad, Md Abul Kalam, Hosen, S M Zahid, Hannan, Md Abdul, Moon, Il Soo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11-12-2019; MDPI
• Subjects: Arylsulfotransferase - chemistry; Arylsulfotransferase - genetics; Binding energy; Binding Sites; Cancer; Computer Simulation; Enzymatic activity; Enzyme Stability; Flexibility; Humans; Hydrophobicity; Leukemia; Ligands; Models, Molecular; Molecular dynamics; Mutation; Mutation - genetics; Polymorphism; Polymorphism, Single Nucleotide - genetics; Principal Component Analysis; Principal components analysis; Protein structure; Protein Structure, Secondary; Proteins; Simulation; Structural stability; Substrate Specificity; Sulfotransferase; Thermodynamics; Xenobiotics; SULT1A1; cancer; R213H; rs9282861; molecular dynamics simulation; binding site
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20246256

Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235-263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages.