Crystallographic studies of inhibitor

Brenk R, Meyer EA, Reuter K, Stubbs MT, Garcia GA, Diederich E, Klebe G. Crystallographic study of inhibitors of tRNA-guanine transglycosylase snggests a new structure-based pharmacophore for virtual screening. J Mol Biol 2004 338 55-75. 

M.T, Garcia, G.A., Diederich, F., and Klebe, G. (2004) Crystallographic study of inhibitors of tRNA-guanine... 

A. E. Eriksson, P. M. Kysiten, T. A. Jones, and A. Liljas, Proteins. 283, 867 (1988). Crystallographic Studies of Inhibitor Binding Sites in Human Carbonk Anhydrase II. A Pen-tacoordinated Binding of the SCN Ion to the Zinc at High pH. 

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. 

Iverson, T.M., Luna-Chavez, C., Croal, L.R., Cecchini, G. and Rees, D.C. (2002) Crystallographic studies of the Eschericia coli quinol-fumarate reductase with inhibitors bound to the quinol-binding site, J. Biol. Chem., 277, 16124-16130. 

The closest organic specie to the inorganic boric acid are the boronic acids generally described as R-B(OH)2. Boronic acids have been shown to act as inhibitors of the subtilisins. X-ray crystallographic studies of phenylboronic acid and phenyl-ethyl-boronic acid adducts with Subtilisin Novo have shown that they contain a covalent bond between the oxygen atom of the catalytic serine of the enzyme and the inhibitor boron atom (Matthews et al, 1975 and Lindquist Terry, 1974). The boron atom is co-ordinated tetrahedrally in the enzyme inhibitor complex. It is likely that boric acid itself interacts with the active site of the subtilisins in the same manner. 

Steitz TA, Henderson R, Blow DM. 1969. Structure of crystalline a-chymotrypsin. 3. Crystallographic studies of substartes and inhibitors bound to the active site of a-chymotrypsin. J Mol Biol 46 337-348. 

The Di Xia research group has completed X-ray crystallographic studies of cytochrome bci with a number of different inhibitors (PDB ISQB, ISQP, ISQQ, ISQV, ISQX). Crystals suitable for crystallography were obtained by co-crystallization of the inhibitor with the native enzyme. Data for two of the inhibitor-modified cytochrome bci complex (PDB ISQP and ISQX) are included in Table 7.6 and Table 7.7. Qne inhibitor-enzyme complex studied by... 

In 2003, the Di Xia group published an X-ray crystallographic study of substrate and inhibitor molecules at the Qo and Qi site. They intended to compare the structure of the native enzyme (PDB INTM) with the cytochrome bci complex having substrate or inhibitors in the Qo and/or Qi sites. The complex with substrate ubiquinone UQ2 (PDB INTZ) was discussed previously in this section. The complex with the inhibitor antimycin Ai (PDB INTK) will be discussed here. A fourth complex with the ubiquinone-model... 

In 2005, the E. A. Berry group published X-ray crystallographic studies of cytochrome bci with bound inhibitors. The structure of PDB 1PP9, resolution 2.23 A, includes stigmatellin A (SMA) in the Qo site and substrate ubiquinone (UQ) in the Qi site, while PDB IPPJ, resolution 2.28 A, includes stigmatellin A in the Qo site and antimycin Ai (ANY) in the Qi site. These... 

J. M. Pisano, J. B. Doherty, P. E. Finke, and K. Hoogsteen, Crystallographic study of a /1-lactam inhibitor complex with... 

Crystallographic studies of native cysteine proteinases and enzyme-inhibitor complexes have been used to interpret much or the kinetic data for cysteine protemsse-caUlyzed hydrolysis of amide bonds. Analysis of the crystal structures of papain [16]. caricain [38], actinidain [56], etc. shows that these structures are closely related. The active site of all these cysteine proteinases contains the Cys-25 sulfhydryl group in close proximity to the His-159 imidazole ring nitrogens, where the latter can abstract the sulfhydryl proton to facilitate attack on the substrate amide carbonyl group [17]. 

N. Borkakoti, The Active Site of Ribonuclease A from the Crystallographic Studies of Ribonuclease A Inhibitor Complexes , Eur. J. Biochem., 132,89 (1983)... 

This evidence has been reinforced recently by an elegant x-ray crystallographic study of the complex formed by trypsin and a polypeptide trypsin inhibitor of the bovine pancreas (25). The complex has proven to be a tetrahedral adduct which is stabilized by hydrogen bonds between the enzyme and the leaving group and by the inability of His-57 (see later) to assume a conformation which would enable it to protonate the leaving group. 

Okamoto Y, et al. Peptide based interleukin-1 beta converting enzyme (ICE) inhibitors synthesis, structure activity relationships and crystallographic study of the ICE-inhibitor complex. Chem. Pharm. Bull. 1999 47 11-21. 

Navia MA, et al. Crystallographic study of a beta-lactam inhibitor complex with elastase at 1.84 A resolution. Nature 1987 327 ... 

These extended-chain ketones are believed to interact with HLE similarity to the aldehyde and TFMK series of inhibitors. Although studies showing that they are true transition-state analogue inhibitors have not been reported, the formation of the covalent hemiketal adduct was documented in an X-ray crystallographic study of a DFK bound to PPE [150]. One notable finding is that the acidic N-terminal substituents first used by Trainor and co-workers to produce TFMKs with good in vivo profiles... 

---