Crystal structure of baff, and use thereof in drug design

A computer for producing a three-dimensional representation of:

• a) a molecule or a molecular complex defined by the structure coordinates of the BAFF amino acids set forth in FIG. 8, or b) a homologue of said molecule or molecular complex, wherein said homologue has a root mean square deviation from the backbone atoms of said amino acids between 0.00 Å and 1.50 Å;
• and
• wherein said computer comprises:
• (i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of the BAFF amino acids set forth in FIG. 8;
• and
• (ii) instructions for processing said machine-readable data into said three-dimensional representation.

A computer for determining the structure coordinates corresponding to X-ray diffraction data obtained from a molecule or molecular complex, wherein said computer comprises:

• a) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of BAFF according to FIG. 8;
• b) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises X-ray diffraction data obtained from said molecule or molecular complex;
• and
• c) instructions for performing a Fourier transform of the machine readable data of (a) and for processing said machine readable data of (b) into structure coordinates.

A computer for producing a three-dimensional representation of:

• a) a molecule or molecular complex comprising a first binding site defined by structure coordinates of a plurality of BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172 according to FIG. 8;
• or
• b) a homologue of said molecule or molecular complex, wherein said homologue comprises a second binding site that has a root mean square deviation from the backbone atoms of a plurality of BAFF amino acids between 0.00 Å and 1.50 Å;
• wherein said computer comprises:
• (i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of said plurality of BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172 according to FIG. 8;
• and
• (ii) instructions for processing said machine-readable data into said three-dimensional representation.

A computer for producing a three-dimensional representation of:

• a) a molecule or molecular complex comprising a first binding site defined by structure coordinates of at least four BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172 according to FIG. 8;
• or
• b) a homologue of said molecule or molecular complex, wherein said homologue comprises a second binding site that has a root mean square deviation from the backbone atoms of said at least four BAFF amino acids of between 0.00 Å and 1.50 Å;
• wherein said computer comprises:
• (i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the structure coordinates of said at least four BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172 according to FIG. 8;
• and
• (ii) instructions for processing said machine-readable data into said three-dimensional representation.

A computer for determining at least a portion of the structure coordinates corresponding to an X-ray diffraction pattern of a molecule or a molecular complex whose structure is unknown, wherein said computer comprises:

• a) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises at least a portion of the structure coordinates according to FIG. 8;
• b) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises an X-ray diffraction pattern of said molecule or molecular complex;
• c) a working memory for storing instructions for processing said machine-readable data of a) and b);
• d) a central processing unit coupled to said working memory and to said machine-readable data of a) and b) for performing a Fourier transform of the machine readable data of (a) and for processing said machine readable data of (b) into structure coordinates;
• and
• e) a display coupled to said central processing unit for displaying said structure coordinates of said molecule of molecular complex.

A method for evaluating the potential of a chemical entity to associate with:

• a) a molecule or molecular complex defined by the structure coordinates of the BAFF amino acids set forth in FIG. 8;
• or b) a homologue of said molecule or molecular complex having a root mean square deviation from the backbone atoms of said amino acids between 0.00 Å and 1.50 Å;
• comprising the steps of:
• (i) employing computational means to perform a fitting operation between said chemical entity and the molecule or molecular complex or said homologue of said molecule or molecular complex;
• and
• (ii) analyzing the results of said fitting operation to quantify the association between said chemical entity and said molecule or molecular complex or said homologue 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 first binding site defined by a plurality of BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172 according to FIG. 8;
• or
• b) a homologue of said molecule or molecular complex comprising a second binding site having a root mean square deviation from the backbone atoms of a plurality of BAFF amino acids between 0.00 Å and 1.50 Å;
• comprising the steps of:
• (i) employing computational means to perform a fitting operation between said chemical entity and said first binding site or said second binding site;
• and
• (ii) analyzing the results of said fitting operation to quantify the association between said chemical entity and said first binding site or said second binding site.

A method for evaluating the potential of a chemical entity to associate with:

• a) a molecule or molecular complex comprising a first binding site defined by at least four BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172 according to FIG. 8;
• or
• b) a homologue of said molecule or molecular complex comprising a second binding site having a root mean square deviation from the backbone atoms of said at least four BAFF amino acids between 0.00 Å and 1.50 Å;
• comprising the steps of:
• (i) employing computational means to perform a fitting operation between said chemical entity and said first binding site or said second binding site;
• and
• (ii) analyzing the results of said fitting operation to quantify the association between said chemical entity and said first binding site or said second binding site.

A method for identifying a potential antagonist of BAFF comprising the steps of:

• a) using structure coordinates of the amino acids of BAFF according to FIG. 8 ± a root mean square deviation from the backbone atoms of said amino acids between 0.00 Å and 1.50 Å, to generate a three-dimensional structure of a molecule or a molecular complex comprising a binding site;
• b) employing said three-dimensional structure to design or select said potential antagonist;
• c) synthesizing said potential antagonist;
• and
• d) contacting said potential antagonist with BAFF to determine the ability of said potential antagonist to interact with BAFF.

A method for identifying a potential antagonist of BAFF comprising the steps of:

• a) using the structure coordinates of a plurality of BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172 according to FIG. 8 or ± a root mean square deviation from the backbone atoms of said plurality of BAFF amino acids between 0.00 Å and 1.50Å, to generate a three-dimensional structure of a molecule or a molecular complex comprising a binding site;
• b) employing said three-dimensional structure to design or select said potential antagonist;
• c) synthesizing said potential antagonist;
• and
• d) contacting said potential antagonist with BAFF to determine the ability of said potential antagonist to interact with BAFF.

A method for identifying a potential antagonist of BAFF comprising the steps of:

• a) using the structure coordinates of at least four BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172 according to FIG. 8 or ± a root mean square deviation from the backbone atoms of said at least four BAFF amino acids between 0.00 Å and 1.50Å, to generate a three-dimensional structure of a molecule or a molecular complex comprising a binding site;
• b) employing said three-dimensional structure to design or select said potential antagonist;
• c) synthesizing said potential antagonist;
• and
• d) contacting said potential antagonist with BAFF to determine the ability of said potential antagonist to interact with BAFF.

A method for evaluating the potential of a variant of an antagonist of BAFF to associate with:

• a) a molecule or a molecular complex defined by the structure coordinates of the BAFF amino acids, set forth in FIG. 8;
• or
• b) a homologue of said molecule or molecular complex having a root mean square deviation from the backbone atoms of said amino acids between 0.00 Å and 1.50 Å;
• comprising the steps of:
• (i) employing computational means to perform a fitting operation between the variant and said molecule or molecular complex;
• and
• (ii) analyzing the results of said fitting operation to quantify the association between said variant and said molecule or molecular complex.

A method for evaluating the potential of a variant of an antagonist of BAFF to associate with:

• a) a first binding site of a molecule or a molecular complex defined by structure coordinates of a plurality of BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172, set forth in FIG. 8;
• or
• b) a homologue of said molecule or molecular complex comprising a second binding site having a root mean square deviation from the backbone atoms of a plurality of BAFF amino acids between 0.00 Å and 1.50 Å;
• comprising the steps of:
• (i) employing computational means to perform a fitting operation between the variant and said first binding site or said second binding site;
• and
• (ii) analyzing the results of said fitting operation to quantify the association between said variant and said first binding site or said second binding site.

A method for evaluating the potential of a variant of an antagonist of BAFF to associate with:

• a) a first binding site of a molecule or a molecular complex defined by structure coordinates of at least four BAFF amino acids selected from the group consisting of His218, Val219, Phe220, Gly221, Asp222, Glu223, Leu224, Ser225, Leu226, Val227, Pro264, Arg265, Glu266, Gly161, Ser162, Tyr163, Ala151, Asp152, Ser153, Glu154, Thr155, Pro156, Leu240, Pro241, Asn242, Ser171 and Phe172, set forth in FIG. 8;
• or
• b) a homologue of said molecule or molecular complex comprising a second binding site having a root mean square deviation from the backbone atoms of said at least four BAFF amino acids between 0.00 Å and 1.50 Å;
• comprising the steps of:
• (i) employing computational means to perform a fitting operation between the variant and said first binding site or said second binding site;
• and
• (ii) analyzing the results of said fitting operation to quantify the association between said variant and said first binding site or said second binding site.

A computer for producing a three-dimensional representation of:

• a) a homology model structure of at least a portion of a molecule whose structure is unknown and at least a portion of whose structure is similar to the structure of BAFF, wherein said homology model structure is defined by at least a portion of the homology model structure coordinates of the APRIL amino acids set forth in FIG. 10;
• wherein said computer comprises:
• (i) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises at least a portion of the structure coordinates of all of the APRIL amino acids set forth in FIG. 10;
• and
• (ii) instructions for processing said machine-readable data into said three-dimensional representation