No abstract

The crystalline State and isometric Operations 1 Symmetry elements 3 Axes of rotational symmetry 3 Axes of rototranslation or screw axes 5 Axes of inversion 5 Axes of rotorefiection 5 Refiection planes with translational component (glide planes) 6 Lattices 6 The rational properties of lattices 7 Crystallographic directions 7 Crystallographic planes 8 Symmetry restrictions due to the lattice periodicity and vice versa 9 Point groups and symmetry classes 11 Point groups in one and two dimensions 16 The Laue classes 17 The seven crystal Systems 17 The Bravais lattices 18 Plane lattices 18 Space lattices 19 The space groups 22 The plane and line groups 30 On the matrix representation of symmetry Operators 32 Appendices: LA The isometric transformations 35 l.B Some combinations of movements 37 l.C Wigner-Seitz cells 41 l.D The space-group rotation matrices l.E Symmetry groups l.F Symmetry generalization References Crystallographic Computing Carmelo Giacovazzo

From a large combinatorial library of chemically constrained bicyclic peptides we isolated a selective and potent (K(i) = 53 nM) inhibitor of human urokinase-type plasminogen activator (uPA) and crystallized the complex. This revealed an extended structure of the peptide with both peptide loops engaging the target to form a large interaction surface of 701 Å(2) with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics.

IQA [[5-oxo-5,6-dihydro-indolo(1,2-a)quinazolin-7-yl]acetic acid] is a novel ATP/GTP site-directed inhibitor of CK2 ('casein kinase 2'), a pleiotropic and constitutively active protein kinase whose activity is abnormally high in transformed cells. The K (i) value of IQA (0.17 microM) is lower than those of other CK2 inhibitors reported so far. Tested at 10 microM concentration in the presence of 100 microM ATP, IQA almost suppresses CK2 activity in vitro, whereas it is ineffective or weakly effective on a panel of 44 protein kinases and on phosphoinositide 3-kinase. In comparison, other CK2 inhibitors, notably apigenin and quercetin, are more promiscuous. The in vivo efficacy of IQA has been assessed by using the fact that treatment of Jurkat cells with IQA inhibits endogenous CK2 in a dose-dependent manner. IQA has been co-crystallized with maize CK2alpha, which is >70% identical with its human homologue, and the structure of the complex has been determined at 1.68 A (1 A=0.1 nm) resolution. The inhibitor lies in the same plane occupied by the purine moiety of ATP with its more hydrophobic side facing the hinge region. Major contributions to the interaction are provided by hydrophobic forces and non-polar interactions involving the aromatic portion of the inhibitor and the hydrophobic residues surrounding the ATP-binding pocket, with special reference to the side chains of V53 (Val53), I66, M163 and I174. Consequently, mutants of human CK2alpha in which either V66 (the homologue of maize CK2alpha I66) or I174 is replaced by alanine are considerably less sensitive to IQA inhibition when compared with wild-type. These results provide new tools for deciphering the enigmatic role of CK2 in living cells and may pave the way for the development of drugs depending on CK2 activity.