Crystal structure of a mutant of cathepsin S enzyme
AssigneeMedivir UK Ltd
InventorsMarieke B.A.C. Lamers, David H. Williams, Johan P. Turkenburg, Roderick E. Hubbard
Life of this patent
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Abstract
The invention relates to the X-ray crystal structure of a cathepsin S mutant. The invention further relates to an apparatus programmed with one or more of the structure coordinates of the cathepsin S binding pockets, wherein said apparatus is capable of displaying a three-dimensional representation of that binding pocket.
Claims44
A crystalline cathepsin S polypeptide, free of any irreversible inhibitor bound thereto.
A crystalline cathepsin S polypeptide comprising the amino acid sequence of any of of SEQ ID NOs:
- 1-8, free of any inhibitor irreversibly bound thereto.
A substantially pure crystalline cathepsin S polypeptide comprising the amino acid sequence of any one of SEQ ID NOs:
- 1-8.
A substantially pure crystalline cathepsin S polypeptide comprising a variant of any one of SEQ ID NOs:
- 1-8, which variant does not possess the activity of cathepsin B, H, K or L.
A cathepsin S polypeptide comprising a variant of the amino acid sequence of any one of SEQ ID NOs:
- 1, 2, 5 and 6, wherein the Cys25 residue is replaced with a Ser residue.
A crystalizable composition comprising a cathepsin S polypeptide which is free of any irreversible inhibitor bound thereto.
An apparatus for producing a three-dimensional representation of:
- a) a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding pocket defined by structure coordinates of cathepsin S amino acids Gly68, Gly69, Phe70, Gly62, Asn63 and Lys64 according to TABLE 3;
- or
- b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, wherein said apparatus comprises:
- i) an input for accessing data that includes the structure coordinates of cathepsin S amino acids Gly68, Gly69, Phe70, Gly62, Asn63 and Lys64 according to TABLE 3;
- ii) a processor for processing said data into said three-dimensional representation;
- and
- iii) a display for displaying said three-dimensional representation generated by said processor.
An apparatus for producing a three-dimensional representation of:
- a) a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding pocket defined by structure coordinates of cathepsin S amino acids Met71, Gly137, Val138, Val162, Gly165 and Phe211 according to TABLE 3;
- or
- b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, said apparatus comprising:
- i) an input for accessing data that includes the structure coordinates of cathepsin S amino acids Met71, Gly137, Val138, Val162, Gly165 and Phe211 according to TABLE 3;
- ii) a processor for processing said data into said three-dimensional representation;
- and
- iii) a display for displaying said three-dimensional representation generated by said processor.
An apparatus for producing a three-dimensional representation of:
- a) a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding pocket defined by structure coordinates of cathepsin S amino acids Gln19, Gly23 and Cys25 according to Table 3;
- or
- c) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, said apparatus comprising:
- i) an input for accessing data that includes the structure coordinates of cathepsin S amino Gln19, Gly23 and Cys2 according to TABLE 3;
- ii) a processor for processing said data into said three-dimensional representation;
- and
- iii) a display for displaying said three-dimensional representation generated by said processor.
An apparatus for determining at least a portion of the structure coordinates corresponding to X-ray diffraction data obtained from a molecule or molecular complex, wherein said apparatus comprises an input for accessing first data that includes at least a portion of the structural coordinates of cathepsin S according to TABLE 3 and;
- a) second data that includes X-ray diffraction data obtained from said molecule or molecular complex;
- b) a processor for performing a Fourier transform of said first data and said second data for processing said first data and said second data into structure coordinates;
- and
- c) a display for displaying said structure coordinates of said molecule or molecular complex.
A method for evaluating the potential of a chemical entity to associate with:
- a) a molecule or molecular complex comprising a binding pocket defined by the coordinates of cathepsin S amino acids Gly68, Gly69, Phe70, Gly62, Asn63 and Lys64 according to TABLE 3;
- or
- b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, comprising the steps of:
- i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket defined by structure coordinates of cathepsin S amino acids Gly68, Gly69, Phe70, Gly62, Asn63 and Lys64 according to TABLE 3, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.54 Å, and
- ii) analyzing the results of said fitting operation to quantify the association between the chemical entity and the binding pocket.
A method for evaluating the potential of a chemical entity to associate with:
- a) a molecule or molecular complex comprising a binding pocket defined by the coordinates of cathepsin S amino acids Met71, Gly137, Val138, Val162, Gly165 and Phe211 according to TABLE 3;
- or
- b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, comprising the steps of:
- i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket defined by structure coordinates of cathepsin S amino acids Met71, Gly137, Val138, Val162, Gly165 and Phe211 according to TABLE 3, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, and
- ii) analyzing the results of said fitting operation to quantify the association between the chemical entity and the binding pocket.
A method for evaluating the potential of a chemical entity to associate with:
- a) a molecule or molecular complex comprising a binding pocket defined by the coordinates of cathepsin S amino acids Met71, Gly137, Val138, Val162, Gly165 and Phe211 according to TABLE 3;
- or
- b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, comprising the steps of:
- i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket defined by structure coordinates of cathepsin S amino acids Gln19, Gly23 and Cys25 according to TABLE 3, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, and
- ii) analyzing the results of said fitting operation to quantify the association between the chemical entity and the binding pocket.
A method for identifying a potential catS inhibitor molecule comprising a cathepsin S S3-like binding pocket comprising the steps of:
- a) using the atomic coordinates of Gly68, Gly69, Phe70, Gly62, Asn63 and Lys64, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, to generate a three-dimensional structure of molecule comprising a cathepsin S S3-like binding pocket;
- b) employing said three-dimensional structure to design or select said potential inhibitor;
- c) synthesizing said inhibitor;
- and
- d) contacting said inhibitor with said molecule to determine the ability of said potential agonist or antagonist to interact with said molecule.
A method for identifying a potential catS inhibitor molecule comprising a cathepsin S S2-like binding pocket comprising the steps of:
- a) using the atomic coordinates of acids Met71, Gly137, Val138, Val162, Gly165 and Phe211, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, to generate a three-dimensional structure of molecule comprising a cathepsin S S2-like binding pocket;
- b) employing said three-dimensional structure to design or select said potential inhibitor;
- c) synthesizing said inhibitor;
- and
- d) contacting said inhibitor with said molecule to determine the ability of said potential inhibitor to interact with said molecule.
A method for identifying a potential catS inhibitor molecule comprising a cathepsin S S1-like binding pocket comprising the steps of:
- a) using the atomic coordinates of acids Gln19, Gly23 and Cys25, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, to generate a three-dimensional structure of molecule comprising a cathepsin S S1-like binding pocket;
- b) employing said three-dimensional structure to design or select said potential inhibitor;
- c) synthesizing said inhibitor;
- and
- d) contacting said inhibitor with said molecule to determine the ability of said potential inhibitor to interact with said molecule.
A method for making a catS inhibitor molecule comprising a cathepsin S S2-like binding pocket comprising the steps of:
- a) using the atomic coordinates of acids Met71, Gly137, Val138, Val162, Gly165 and Phe211, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, to generate a three-dimensionsal structure of molecule comprising a cathepsin S S2-like binding pocket;
- b) employing said three-dimensional structure to design or select said potential inhibitor;
- c) synthesizing said inhibitor.
A method for producing a potential catS inhibitor molecule comprising a cathepsin S S3-like binding pocket comprising the steps of:
- a) using the atomic coordinates of Gly68, Gly69, Phe70, Gly62, Asn63 and Lys64, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, to generate a three-dimensional structure of molecule comprising a cathepsin S S3-like binding pocket;
- b) employing said three-dimensional structure to design or select said potential inhibitor;
- c) synthesizing said inhibitor.
A method for producing a potential catS inhibitor molecule comprising a cathepsin S S1-like binding pocket comprising the steps of:
- a) using the atomic coordinates of Gln19, Gly23 and Cys25, plus or minus a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, to generate a three-dimensional structure of molecule comprising a cathepsin S S1-like binding pocket;
- b) employing said three-dimensional structure to design or select said potential inhibitor;
- c) synthesizing said inhibitor.
Dependencies are inferred from the claim text.