Side-By-Side Surf

- Darrell Hurt

Description of Image:

The image shows inositol 1,4,5-trisphosphate 3-kinase (IP3K) on the left and phosphatidylinositol phosphate kinase type II beta (PIPK2b) on the right.  Despite the lack of significant primary sequence similarity, a Dali search among known protein structures revealed that PIPK2b is the most similar structure known.  The r.m.s.d. for the imposition of 131 C-alphas between the two structures is 4.1 angstroms.  IP3K (brick red) phosphorylates only soluble inositides and is found in monomeric form, whereas PIPK2b exists as a dimer (gold and forest green) that phosphorylates inositides found only in membranes.  The large flat bottom of PIPK2b facilitates this function.  IP3K contains a unique helical domain (marine) that collides with the membrane when docked in the same orientation as PIPK2b.  Given the size of the helical domain and its insertion on what would be the membrane-proximal face of the kinase, it is not reasonable to expect that this domain could move out of the way.  Thus membrane-bound phosphoinositide phosphorylation is inhibited by a direct steric blockade via the helical domain.

(Note: reproduced with permission from the journal. Crystal Structure of the Catalytic Core of Inositol 1,4,5-Trisphosphate 3-Kinase,  Gregory J. Miller and James H. Hurley, Molecular Cell, 15, (2004), 703-711.)