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Residue propensities, discrimination and binding site prediction of adenine and guanine phosphates.

Firoz A, Malik A, Joplin KH, Ahmad Z, Jha V, Ahmad S - BMC Biochem. (2011)

Bottom Line: This is likely to miss those where a similar binding site has not been previously characterized and when the binding sites do not follow the rule described by predefined motif.Results indicate that subtle differences exist between single residue preferences for specific nucleotides and taking neighbor environment and evolutionary context into account, successful models of their binding site prediction can be developed.This is expected to be helpful in identifying novel binding sites for adenine and guanine phosphates, especially when a known binding motif is not detectable.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomedical Informatics Center, PGIMER, Chandigarh-160012, India. adeel@netasa.org

ABSTRACT

Background: Adenine and guanine phosphates are involved in a number of biological processes such as cell signaling, metabolism and enzymatic cofactor functions. Binding sites in proteins for these ligands are often detected by looking for a previously known motif by alignment based search. This is likely to miss those where a similar binding site has not been previously characterized and when the binding sites do not follow the rule described by predefined motif. Also, it is intriguing how proteins select between adenine and guanine derivative with high specificity.

Results: Residue preferences for AMP, GMP, ADP, GDP, ATP and GTP have been investigated in details with additional comparison with cyclic variants cAMP and cGMP. We also attempt to predict residues interacting with these nucleotides using information derived from local sequence and evolutionary profiles. Results indicate that subtle differences exist between single residue preferences for specific nucleotides and taking neighbor environment and evolutionary context into account, successful models of their binding site prediction can be developed.

Conclusion: In this work, we explore how single amino acid propensities for these nucleotides play a role in the affinity and specificity of this set of nucleotides. This is expected to be helpful in identifying novel binding sites for adenine and guanine phosphates, especially when a known binding motif is not detectable.

Show MeSH
Adenine and Guanine phosphates (nucleotides) found in complex with proteins in Protein Data Bank, with corresponding HETATM (three-letter) codes.
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Figure 1: Adenine and Guanine phosphates (nucleotides) found in complex with proteins in Protein Data Bank, with corresponding HETATM (three-letter) codes.

Mentions: Adenine triphosphate (ATP) is widely known to be energy currency of biological molecules as its conversion to corresponding di- and mono-phosphate leads to energy release, commonly used in conformational changes required for many biological interactions [1,2]. Closely related molecules such as guanidine triphosphate (GTP) also have similar metabolic implications [3,4]. Use of GTP versus ATP is highly specific to organisms as well as pathways [5]. Since, adenine and guanine have similar structures (both are purines) and essentially differ from each other by a nitrogenous versus oxygen group [5], (See Figure 1), a high degree of specificity between them is quite surprising and not well understood. A thorough understanding of this specificity therefore has wide biological implications, including discovery of metabolic drug targets as well as inhibitor design. There are other areas of biological research, where these molecules play a role such as cell-signaling and cofactor activity [6-11]. Thus, adenine and guanine phosphates form an important group of molecules, whose interactions with proteins at single residue as well as sequence and structural motifs levels have great significance but the process of this specificity lacks clear understanding. Discovery of binding sites for each of these molecules lies at the heart of this problem and it is essential to identify such binding sites for targeting inhibitors or understanding their function.


Residue propensities, discrimination and binding site prediction of adenine and guanine phosphates.

Firoz A, Malik A, Joplin KH, Ahmad Z, Jha V, Ahmad S - BMC Biochem. (2011)

Adenine and Guanine phosphates (nucleotides) found in complex with proteins in Protein Data Bank, with corresponding HETATM (three-letter) codes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113737&req=5

Figure 1: Adenine and Guanine phosphates (nucleotides) found in complex with proteins in Protein Data Bank, with corresponding HETATM (three-letter) codes.
Mentions: Adenine triphosphate (ATP) is widely known to be energy currency of biological molecules as its conversion to corresponding di- and mono-phosphate leads to energy release, commonly used in conformational changes required for many biological interactions [1,2]. Closely related molecules such as guanidine triphosphate (GTP) also have similar metabolic implications [3,4]. Use of GTP versus ATP is highly specific to organisms as well as pathways [5]. Since, adenine and guanine have similar structures (both are purines) and essentially differ from each other by a nitrogenous versus oxygen group [5], (See Figure 1), a high degree of specificity between them is quite surprising and not well understood. A thorough understanding of this specificity therefore has wide biological implications, including discovery of metabolic drug targets as well as inhibitor design. There are other areas of biological research, where these molecules play a role such as cell-signaling and cofactor activity [6-11]. Thus, adenine and guanine phosphates form an important group of molecules, whose interactions with proteins at single residue as well as sequence and structural motifs levels have great significance but the process of this specificity lacks clear understanding. Discovery of binding sites for each of these molecules lies at the heart of this problem and it is essential to identify such binding sites for targeting inhibitors or understanding their function.

Bottom Line: This is likely to miss those where a similar binding site has not been previously characterized and when the binding sites do not follow the rule described by predefined motif.Results indicate that subtle differences exist between single residue preferences for specific nucleotides and taking neighbor environment and evolutionary context into account, successful models of their binding site prediction can be developed.This is expected to be helpful in identifying novel binding sites for adenine and guanine phosphates, especially when a known binding motif is not detectable.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomedical Informatics Center, PGIMER, Chandigarh-160012, India. adeel@netasa.org

ABSTRACT

Background: Adenine and guanine phosphates are involved in a number of biological processes such as cell signaling, metabolism and enzymatic cofactor functions. Binding sites in proteins for these ligands are often detected by looking for a previously known motif by alignment based search. This is likely to miss those where a similar binding site has not been previously characterized and when the binding sites do not follow the rule described by predefined motif. Also, it is intriguing how proteins select between adenine and guanine derivative with high specificity.

Results: Residue preferences for AMP, GMP, ADP, GDP, ATP and GTP have been investigated in details with additional comparison with cyclic variants cAMP and cGMP. We also attempt to predict residues interacting with these nucleotides using information derived from local sequence and evolutionary profiles. Results indicate that subtle differences exist between single residue preferences for specific nucleotides and taking neighbor environment and evolutionary context into account, successful models of their binding site prediction can be developed.

Conclusion: In this work, we explore how single amino acid propensities for these nucleotides play a role in the affinity and specificity of this set of nucleotides. This is expected to be helpful in identifying novel binding sites for adenine and guanine phosphates, especially when a known binding motif is not detectable.

Show MeSH