X-ray analyses of aspartic proteinases. III Three-dimensional structure of endothiapepsin complexed with a transition-state isostere inhibitor of renin at 1.6 A resolution.

摘要: The aspartic proteinase, endothiapepsin (EC 3.4.23.6), was complexed with a highly potent renin inhibitor, H-261 (t-Boc-His-Pro-Phe-His-Leu OH Val-Ile-His), where denotes hydroxyethylene (-(S) CHOH-CH2-) transition-state isostere in the scissile bond surrogate. Crystals were grown form that has same space group P21 as uncomplexed enzyme, but 10 A decrease length of a-axis and 13° β-angle. X-ray data have been collected to resolution 1·6 A. rotation translation parameters defining position enzyme unit cell determined previously using another enzyme-inhibitor complex crystallized isomorphously H-261. molecule refined restrained least-squares refinement positions non-hydrogen atoms inhibitor water molecules defined by difference Fourier techniques. 322 further crystallographic R-factor 0·14. Apart from small rigid domain comprising residues 190 302 movements flap, there is little conformation between forms enzyme. bound an extended along active site cleft, hydroxyl moiety hydrogen-bonded both catalytic aspartate carboxylates. stabilized hydrogen bonds mainchain All side-chains are van der Waals' contact groups define series specificity pockets cleft. study provides useful clues how this (IC50 value 0·7 × 10−9 M) may bind renin. In particular it defines interactions more precisely than possible therefore insight into transition state complex.