PDBsum entry 1h3b

Isomerase

PDB id: 1h3b

Contents

Protein chains

620 a.a. *

Ligands

C8E ×3

R46 ×3

Waters ×208

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Binding structures and potencies of oxidosqualene cyclase inhibitors with the homologous squalene-Hopene cyclase.

Authors

A.Lenhart, D.J.Reinert, J.D.Aebi, H.Dehmlow, O.H.Morand, G.E.Schulz.

Ref.

J Med Chem, 2003, 46, 2083-2092. [DOI no: 10.1021/jm0211218]

PubMed id

12747780

Abstract

The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the structures were elucidated by X-ray diffraction analyses. All inhibitors were bound in the large active center cavity. The detailed binding structures are presented and discussed in the light of the IC50 values of these 11 as well as 17 other inhibitors. They provide a consistent picture for the inhibition of the bacterial enzyme and can be used to adjust and improve homology models of the human enzyme. The detailed active center structures of the two enzymes are too different to show an IC50 correlation.

Secondary reference #1

Title

Crystal structure of a squalene cyclase in complex with the potential anticholesteremic drug ro48-8071.

Authors

A.Lenhart, W.A.Weihofen, A.E.Pleschke, G.E.Schulz.

Ref.

Chem Biol, 2002, 9, 639-645. [DOI no: 10.1016/S1074-5521(02)00138-2]

PubMed id

12031670

Figure 2.
Figure 2. Ribbon Model of SHC with a Space-Filling Model of Bound Ro48-8071Fluorine is green; bromine is purple. The inner and outer helices are yellow and red, respectively. The channel constriction residues, the putative catalytic acid Asp376 [4], and the photolabeled Ala44 [18] are shown as light-green ball-and-stick models. The nonpolar plateau, assumed to plunge into the nonpolar membrane interior, consists of helices α8 and 3[10] as well as loops L6′, L8, and L15. It harbors the channel entrance (E), indicated by a dotted line.

Figure 4.
Figure 4. Surface Representation of SHC Sliced through the Middle of the MoleculeThe surfaces are colored as nonpolar (yellow) and positively (blue) and negatively (red) charged. The large internal cavity is connected by a nonpolar channel to a hydrophobic surface patch that dips into the membrane. The channel constriction (C) permits substrate passage because Phe434 and Cys435 are on a mobile loop. Ro48-8071 (major conformation) occupies the active-center cavity and the channel up to the constriction. Asp376 and Ala44 are shown as ball-and-stick models.

The above figures are reproduced from the cited reference with permission from Cell Press

Secondary reference #2

Title

The structure of the membrane protein squalene-Hopene cyclase at 2.0 a resolution.

Authors

K.U.Wendt, A.Lenhart, G.E.Schulz.

Ref.

J Mol Biol, 1999, 286, 175-187. [DOI no: 10.1006/jmbi.1998.2470]

PubMed id

9931258

Figure 6.
Figure 6. Surface representations [Nicholls et al 1991] of the two structurally known monotopic membrane proteins color-coded for non-polar (yellow), positive (blue) and negative (red) areas. (a) Proposed model for SHC-binding to the membrane. The two non-polar plateaux are oriented in parallel and reach with their channel entrances E into the non-polar part of the membrane where squalene is dissolved. The non-polar pocket binding a C[8]E[4] molecule at the interface is marked by an x. (b) View from the membrane onto the two non-polar plateaux of the SHC dimer. Four ligated C[8]E[4] detergent molecules are included. (c) View from the membrane onto dimeric prostaglandin-H[2] synthase-I with the ligated detergent b-octylglucoside [Loll et al 1995]. The arrows indicate the presumed passage for the polar headgroup of the substrate arachidonic acid from the lipid bilayer to the entrance of the active center pocket.

Figure 11.
Figure 11. Stereo view of the structure consisting of QW-repeat r6 together with the front region of r7. Two outer (red) and one inner (yellow) barrel-helices are depicted with one core region (green, residues drawn out to the C^b atom). Hydrogen bonds are represented by dots. For the core regions, the average deviation of all pairwise comparisons except r4 is 0.23 Å, which is around the error limit. The core of r4 forms a long loop that returns to the tryptophan position, which however, carries a phenylalanine (Figure 10).

The above figures are reproduced from the cited reference with permission from Elsevier

Secondary reference #3

Title

Structure and function of a squalene cyclase.

Authors

K.U.Wendt, K.Poralla, G.E.Schulz.

Ref.

Science, 1997, 277, 1811-1815. [DOI no: 10.1126/science.277.5333.1811]

PubMed id

9295270

Figure 1.
Fig. 1. The proposed reaction steps in squalene-hopene cyclases involving carbocationic intermediates. The general acid B[1]:H protonates (H) squalene at C3, whereas the general base B[2] deprotonates at C29 of the hopenyl cation. In a side reaction, the cation is hydroxylated^ forming hopan-22-ol.

Figure 5.
Fig. 5. The color-coded surface representations (30) with nonpolar (yellow), positive (blue), and negative (red) areas. (A) View similar to Fig. 2 but rotated around a vertical axis and^ sliced. The cutting plane (checked) opens the large internal cavity with the bound inhibitor LDAO. The nonpolar channel runs to the^ left, opening into a nonpolar plateau. The channel constriction (C) appears closed, but it is mobile enough to be readily opened. At the upper left, hopane (two views) is shown at scale. (B) View similar to Fig. 2 directly onto the 1600 Å2 nonpolar plateau with the channel entrance (E) at its center and two nonpolar side chains pointing to the outside. This is the only large nonpolar region on the surface.

The above figures are reproduced from the cited reference with permission from the AAAs

Secondary reference #4

Title

Ro 48-8.071, A new 2,3-Oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, Squirrel monkeys, And minipigs: comparison to simvastatin.

Authors

O.H.Morand, J.D.Aebi, H.Dehmlow, Y.H.Ji, N.Gains, H.Lengsfeld, J.Himber.

Ref.

J Lipid Res, 1997, 38, 373-390.

PubMed id

9162756