Fig. 8

Model of Rab11 activation by SH3BP5. In the GDP-bound state switch I (SWI) directly interacts with bound nucleotide, with F36 having a key role in stabilizing this interaction. Upon SH3BP5 binding, switch I undergoes a large conformational rearrangement, with F36 and I44 forming hydrophobic contacts with SH3BP5, leading to exposure of the nucleotide-binding pocket. F36 and I44 are in a highly constrained orientation and require the interspersing residues to allow for formation of this interface. Similar to the Ypt7 GEF Mon1-ccz1⁴⁴ the K41 residue projects into the Mg²⁺-binding pocket. The lack of clear electron density around K41 is indicated by being colored in gray, to indicate ambiguity in its exact positioning. There are limited conformational changes in switch II upon SH3BP5 binding, with the hydroxyl from Y73 in position to cap the switch I helix. Upon SH3BP5 disengagement, Mg²⁺ and GTP can enter the nucleotide-binding pocket, with active Rab11 able to bind and recruit downstream effectors