It has been suggested the DFD theme makes it harder for ATP to access to the binding site. Indeed, three dimensional crystal structure studies of the areas of Mnk1 and Mnk2, as shown in Figure 5A and 5B, indicates that the DFD motif is rotated by natural product libraries 180 in comparison with the DFG motif of other protein kinases. The Phe227 inside the Mnk2 KR inserts into the ATP binding pocket, stopping ATP from entering this binding site. That non canonical arrangement of the DFD pattern is referred to as the DFG/D OUT conformation, when compared with the standard DFG/D IN conformation found in other active kinases. Interestingly, the design of Mnk2 KR, where Asp228 was replaced with a glycine residue, showed that it could now adopt DFG/D OUT conformations and both DFG/D IN. As shown in Figure 5C, the Mnk1 KR shows similar architectural characteristics Lymph node to Mnk2 KR, but, the N terminal lobe of Mnk2 KR is tilted by approximately 10 degrees, making the kinase binding pocket somewhat more open to accommodate ATP or perhaps a small molecule inhibitor in comparison to Mnk1 KR. Mnks are architecturally different from almost every other protein kinases, a feature which can be exploited for design of highly selective Mnk inhibitors, whilst the DFG/D OUT conformation of Mnk2 is specific to the chemical free protein kinase. Analysis of the company crystal structure of staurosporine in Mnk2 KR revealed that staurosporine binds in the canonical ATP active site in a manner similar to its known binding mode in other protein kinases. The polycyclic ring system of staurosporine is sandwiched between the N terminal and C terminal lobes. The 1 NH and 5 O atoms of staurosporine type hydrogen bonds to the backbone remains of Glu160 and Met162 within the hinge region. The structural information is invaluable for that construction based design of novel Mnk inhibitors. Many small molecule kinase inhibitors developed so far act as ATP opponents targeting the ATP CX-4945 ic50 binding site, using their respective kinases following an identical conformation to that used to bind ATP. These inhibitors are now and again referred as type I kinase inhibitors. The scaffold of ATP aggressive inhibitors or type I inhibitors often consists of planar heterocyclic systems that act as mimetics for the adenine moiety of ATP. They always contain characteristic surrounding hydrogen bond donor and acceptor groups in the hinge region, the part that connects the D and C terminal kinase areas, along with hydrophobic functions. Many ATP competitive inhibitors have been successfully produced as therapeutics. But, due to the highly conserved structure of the ATP binding domain generally in most kinases, these inhibitors usually suffer from cross reactivity with other kinases, causing poor safety and often serious unwanted effects.