title: Molecular dynamics investigation on the poor sensitivity of A171T mutant NEDD8-activating enzyme (NAE) for MLN4924.
abstract: MLN4924 is an adenosine sulfamate analog that generates the inhibitory NEDD8-MLN4924 covalent complex. A single nucleotide transition that changes alanine 171 to threonine (A171T) of the NAE subunit UBA3 reduces the enzyme's sensitivity for MLN4924. Our molecular dynamics simulation study revealed that A171T transition brought remarkable conformational changes in enzyme structure (open ATP binding pocket), which reduced the interaction between MLN4924 and ATP binding pocket while wild form completely covered the MLN4924. A total difference of -49.75 kJ/mol was noticed in interaction energy (electrostatic and van der Waals) during simulation between mutant and wild form with MLN4924. Superimposition of final 20 ns mutant structure with reference structure showed significant change in native binding position as compared to wild form. Results were found in coherence with the recently reported in vitro studies which states that A171T transition leads to change in ATP binding pocket structure.
authors.affiliation: a School of Biochemical Engineering, Indian Institute of Technology, Banaras Hindu University , Varanasi 221005 , India .
authors.forename: Sharad
authors.initials: S
authors.lastname: Verma
authors.forename: Amit
authors.initials: A
authors.lastname: Singh
authors.forename: Abha
authors.initials: A
authors.lastname: Mishra
mesh_terms: D003517:Cyclopentanes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics
chemical_list: D003517:Cyclopentanes; D011743:Pyrimidines; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat
keywords: A171T mutant NAE; MLN4924; NEDD8-activating enzyme; essential dynamics; molecular dynamics simulation