Mannosidase structures
OwnerDavid Richard Rose, Douglas Arthur Kuntz +1inventors
InventorsDavid Richard Rose, Douglas Arthur Kuntz, Jean Maria Hubertus Van Den Elsen
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Abstract
The present invention relates to a crystal comprising a mannosidase II ligand-binding domain. In particular the present invention relates to a crystal comprising mannosidase II (with and without swainsonine), and its use to generate models for elucidating the structure of other polypeptides and for better identifying ligands capable of modulating mannosidase II activity.
Claims47
A crystal comprising a mannosidase II ligand-binding domain.
A crystal according to any preceding claim, wherein the crystal has P21 symmetry.
A crystal according to any preceding claim, wherein said crystal comprises a unit cell having the following dimensions:
- a=69 (±5) Å, b=110 (±5) Å, c=139 (±5) Å.
A crystal according to any preceding claim having the structural coordinates as shown in Table 1, Table 2, or Table 8.
A crystal comprising swainsonine or a derivative thereof having the structural coordinates as shown in Table 2 or Table 8.
Machine readable media encoded with data representing the structural coordinates of a crystal or ligand binding domain according to any of the preceding claims.
A modulator of the activity of a mannosidase II derived from a crystal as claimed in any of the preceding claims.
A method for identifying a potential modulator of a mannosidase II, or ligand binding domain thereof, comprising the step of using the structural coordinates of Table 1, 2, or 8 that define a mannosidase II or ligand binding domain thereof, to computationally evaluate a test compound for its ability to associate with the mannosidase II or ligand binding domain, wherein a test compound that associates is a potential modulator of a mannosidase II.
A method for identifying a modulator of a mannosidase II by determining binding interactions between a test compound and binding site of a ligand binding domain of a mannosidase II as defined in Table 4 comprising:
- (a) generating the binding site on a computer screen;
- (b) generating a test compound with its spatial structure on the computer screen;
- and
- (c) testing to determine whether the test compound binds to a selected number of atomic contacts in a binding site.
A method for identifying a potential modulator of a mannosidase II function comprising the steps:
- (a) docking a computer representation of a test compound from a computer data base with a computer representation of a crystal of a mannosidase II as claimed in the preceding claims, to obtain complexes;
- (b) determining conformations of complexes with a favourable geometric fit and favourable complementary interactions;
- and
- (c) identifying a conformation of a compound that best fits the selected site as a potential modulators of the mannosidase II.
A method for identifying a potential modulator of a mannosidase II function comprising the steps:
- (a) modifying a computer representation of a test compound complexed with a crystal of a ligand binding domain of a mannosidase II as described in any of the preceding claims, by deleting or adding a chemical group or groups;
- (b) determining a conformation of the complex with a favourable geometric fit and favourable complementary interactions;
- and
- (c) identifying a compound that best fits the binding site as a potential modulator of a mannosidase II.
A method for identifying a potential modulator of a mannosidase II function co comprising the steps:
- (a) selecting a computer representation of a test compound complexed with a crystal of a ligand binding domain of a mannosidase II as defined in the preceding claims;
- and
- (b) searching for molecules in a data base that are similar to the test compound using a searching computer program, or replacing portions of the test compound with similar chemical structures from a data base using a compound building computer program.
A modulator of a mannosidase II identified by a method according to any of the preceding claims.
A modulator of a mannosidase II based on the three-dimensional structure of an inhibitor's spatial association with a crystal as claimed in any of the preceding claims.
A method for designing potential inhibitors of a mannosidase II comprising the step of using the structural coordinates of a mannosidase II inhibitor defined in relation to its spatial association with a crystal of a mannosidase II or a ligand binding domain thereof according to any of the preceding claims, to generate a compound that is capable of associating with the mannosidase II or ligand binding domain thereof.
A pharmaceutical composition comprising a modulator according to any of the preceding claims either alone or with other active substances.
Plasmid pCopBlast.
Dependencies are inferred from the claim text.