ABSTRACT This study used AlphaFold2 to investigate allosteric structural changes during c‐Abl transactivation. Two structural forms of c‐Abl (positions of SH2 and SH3 domains relative to kinase domain) and four active site types (types 0–3) were identified. Key interactions were predicted between the c‐Crk SH3 domain (CrkSH3N) and four c‐Abl PxxPxK/R motifs, particularly the 612–617 motif, where residue 617R plays a critical role. A residue‐level analysis using our developed PAEⱼson2excel tool supported these findings. The predicted CrkSH3N position relative to c‐Abl kinase domain varied. The c‐Abl's active site displayed structural flexibility, categorized into four types on the basis of the presence or absence of residues 286E and 381D within the hydrogen‐bond distance (3. 2 Å) to the side‐chain nitrogen of 271K: type 0 (neither 286E nor 381D), type 1 (286E present), type 2 (381D present), and type 3 (both 286E and 381D present). The Abl (SH3W110K) may coincide with the presence of type 1 in the c‐Abl mutant alone and may display types 0–3 when complexed. Multiple interactions between CrkSH3N and c‐Abl PxxPxK/R motifs may coincide with the presence of type 2. These findings provide new insights into the dynamic flexibility of the c‐Abl active site during c‐Abl transactivation.
Shishido et al. (Sat,) studied this question.