Fig. 21.16 The crystal structures with the 4-substituted lin-benzoguanine derivatives show that the basic nitrogen in the chain is incorporated into an H-bonding network with the water cluster and with Asp 280 (top). At first glance, 21.23 and 21.24 appear to adopt an almost identical binding mode. On closer inspection, however, there is a crucial difference that, as was later shown, is of great importance for the stability of the protein (bottom). The cyclohexyl ring (blue) in 21.24 occupies a slightly larger space than the five-membered ring (ochre) in 21.23, displacing Val 45 from its position in the uncomplexed protein (see red arrows). The cyclopentyl ring in 21.23 is slightly smaller, so it does not cause this displacement. When Val 45 is dislocated, it continues like a series of dominoes, first on Thr 47 (red arrows) and then on the entire loop with the attached helix, which becomes disordered at the end. It can no longer be seen in an orderly fashion in the crystal structure (in the blue structure, this part is missing in the region of the ellipse, whereas it is clearly visible in the ochre structure). As will be shown later, this breakdown of the ordered structure of the loop-helix motif has a massive influence on the dimer stability of the enzyme.