Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.

摘要: Overexpression of mitotic arrest-deficient proteins Mad1 and Mad2, two components spindle assembly checkpoint, is a risk factor for chromosomal instability (CIN) trigger many genetic disorders. Mad2 transition from inactive open (O-Mad2) to active closed (C-Mad2) conformations or binding specific partners (cell-division cycle protein 20 (Cdc20) Mad1) were targets previous pharmacogenomics studies. Here, Cdc20 the interconversion rate predicted molecular features with critical contribution these processes determined by extending quantitative structure-activity relationship (QSAR) method large-size such as Mad2. QSAR models built based on available published data 23 mutants inducing CIN-related functional changes. The most relevant descriptors identified predicting native action mechanism their involvement in disorders are steric (van der Waals area solvent accessible subdivided) energetic van energy descriptors. reliability our indicated significant values statistical coefficients: Cross-validated correlation q2 (0.53–0.65) fitted r2 (0.82–0.90). Moreover, established equations, we rationally design analyze nine de novo possible promoters CIN.