Phosphoinositide-specific phospholipase Cs (PI-PLCs) are critical regulatory enzymes in eukaryotes which are proximal targets of activation by receptor tyrosine kinases and by G-protein-coupled receptors. We have expressed, crystallized, and determined the structure of the three-domain core of rat phosphoinositide-specific phospholipase C-delta1 at 2.4 Angstroms resolution in the triclinic crystal form. The stereochemical relationship between the three domains is essentially identical in two different crystal forms. The Ca2+ analogue Sm3+ binds at two sites between the jaws of the C2 domain. Sm3+ binding triggers a conformational change in which sections of the C2 jaws move apart, opening the mouth by 9 Angstroms and creating a gap large enough to bind a phospholipid headgroup. 3-isopropylmalate dehydrogenase (IMDH) and isocitrate dehydrogenase (IDH) belong to a unique class of metal-dependent decarboxylating dehydrogenases. A. M. Dean has fully altered the specificity of NADP+- dependent IDH in favor of NAD+ by mutagenesis, and also inverted the specificity of NAD+-dependent IMDH. We have determined the structures of both the engineered IDH and the IMDH in complex with NAD+ and NADP+, respectively. The structure of redesigned IMDH illustrates the successful creation of a new 2'-phosphate binding site. The structure of the engineered NAD+-specific IDH shows that NADP+ affinity is destroyed by removing favorable interactions and by adding a repulsive interaction with Asp344. The specificity change requires a series of changes in steric packing interactions. The linchpin for repacking in the adenosine binding site is residue 351. The side-chain of this """"""""second layer"""""""" residue dictates packing of the surrounding """"""""first layer"""""""" residues which interact with the 2' moiety and, in turn, directly determine specificity.
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