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Structural analysis of inhibition of E. coli methionine aminopeptidase: implication of loop adaptability in selective inhibition of bacterial enzymes.

Ma ZQ, Xie SX, Huang QQ, Nan FJ, Hurley TD, Ye QZ - BMC Struct. Biol. (2007)

Bottom Line: When compared with the human isozymes, this loop either becomes buried in the human type I enzyme due to an N-terminal extension that covers its position or is replaced by a unique insert in the human type II enzyme.The adaptability of the YHGY loop in E. coli methionine aminopeptidase, and likely in other bacterial methionine aminopeptidases, enables the enzyme active pocket to accommodate inhibitors of differing size.The differences in this adaptable loop between the bacterial and human methionine aminopeptidases is a structural feature that can be exploited to design inhibitors of bacterial methionine aminopeptidases as therapeutic agents with minimal inhibition of the corresponding human enzymes.

View Article: PubMed Central - HTML - PubMed

Affiliation: High Throughput Screening Laboratory, University of Kansas, Lawrence, Kansas 66047, USA. zeqiang.ma@vanderbilt.edu

ABSTRACT

Background: Methionine aminopeptidase is a potential target of future antibacterial and anticancer drugs. Structural analysis of complexes of the enzyme with its inhibitors provides valuable information for structure-based drug design efforts.

Results: Five new X-ray structures of such enzyme-inhibitor complexes were obtained. Analysis of these and other three similar structures reveals the adaptability of a surface-exposed loop bearing Y62, H63, G64 and Y65 (the YHGY loop) that is an integral part of the substrate and inhibitor binding pocket. This adaptability is important for accommodating inhibitors with variations in size. When compared with the human isozymes, this loop either becomes buried in the human type I enzyme due to an N-terminal extension that covers its position or is replaced by a unique insert in the human type II enzyme.

Conclusion: The adaptability of the YHGY loop in E. coli methionine aminopeptidase, and likely in other bacterial methionine aminopeptidases, enables the enzyme active pocket to accommodate inhibitors of differing size. The differences in this adaptable loop between the bacterial and human methionine aminopeptidases is a structural feature that can be exploited to design inhibitors of bacterial methionine aminopeptidases as therapeutic agents with minimal inhibition of the corresponding human enzymes.

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Distribution of B factors over the residues of the complex structures. Only B-factors for Cα carbons are shown.
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Figure 5: Distribution of B factors over the residues of the complex structures. Only B-factors for Cα carbons are shown.

Mentions: The YHGY loop (Y62, H63, G64, and Y65) forms part of the substrate and inhibitor binding pocket and has direct contact with the bound inhibitors. Positional uncertainty of these atoms in the structures is reflected in their B-factors. The B-factor values of atoms in this loop refined to high values in some of the structures (2EVM, 2EVC, 2Q92, 2Q94), indicating that these atoms are not as well ordered in those structures as in others (Fig. 5). However, the same atoms in some of the structures (2Q93, 2Q96) have low B-factors. The atoms in the YHGY loop do not consistently show high value for B-factors in the presence of a bound inhibitor, in comparison with other parts of the molecule. One of the reasons for this observation is that the value of B-factor is affected by interactions of the atom with the bound inhibitor. Therefore, the absolute value of their B-factors is not a good indicator of their adaptability.


Structural analysis of inhibition of E. coli methionine aminopeptidase: implication of loop adaptability in selective inhibition of bacterial enzymes.

Ma ZQ, Xie SX, Huang QQ, Nan FJ, Hurley TD, Ye QZ - BMC Struct. Biol. (2007)

Distribution of B factors over the residues of the complex structures. Only B-factors for Cα carbons are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2238726&req=5

Figure 5: Distribution of B factors over the residues of the complex structures. Only B-factors for Cα carbons are shown.
Mentions: The YHGY loop (Y62, H63, G64, and Y65) forms part of the substrate and inhibitor binding pocket and has direct contact with the bound inhibitors. Positional uncertainty of these atoms in the structures is reflected in their B-factors. The B-factor values of atoms in this loop refined to high values in some of the structures (2EVM, 2EVC, 2Q92, 2Q94), indicating that these atoms are not as well ordered in those structures as in others (Fig. 5). However, the same atoms in some of the structures (2Q93, 2Q96) have low B-factors. The atoms in the YHGY loop do not consistently show high value for B-factors in the presence of a bound inhibitor, in comparison with other parts of the molecule. One of the reasons for this observation is that the value of B-factor is affected by interactions of the atom with the bound inhibitor. Therefore, the absolute value of their B-factors is not a good indicator of their adaptability.

Bottom Line: When compared with the human isozymes, this loop either becomes buried in the human type I enzyme due to an N-terminal extension that covers its position or is replaced by a unique insert in the human type II enzyme.The adaptability of the YHGY loop in E. coli methionine aminopeptidase, and likely in other bacterial methionine aminopeptidases, enables the enzyme active pocket to accommodate inhibitors of differing size.The differences in this adaptable loop between the bacterial and human methionine aminopeptidases is a structural feature that can be exploited to design inhibitors of bacterial methionine aminopeptidases as therapeutic agents with minimal inhibition of the corresponding human enzymes.

View Article: PubMed Central - HTML - PubMed

Affiliation: High Throughput Screening Laboratory, University of Kansas, Lawrence, Kansas 66047, USA. zeqiang.ma@vanderbilt.edu

ABSTRACT

Background: Methionine aminopeptidase is a potential target of future antibacterial and anticancer drugs. Structural analysis of complexes of the enzyme with its inhibitors provides valuable information for structure-based drug design efforts.

Results: Five new X-ray structures of such enzyme-inhibitor complexes were obtained. Analysis of these and other three similar structures reveals the adaptability of a surface-exposed loop bearing Y62, H63, G64 and Y65 (the YHGY loop) that is an integral part of the substrate and inhibitor binding pocket. This adaptability is important for accommodating inhibitors with variations in size. When compared with the human isozymes, this loop either becomes buried in the human type I enzyme due to an N-terminal extension that covers its position or is replaced by a unique insert in the human type II enzyme.

Conclusion: The adaptability of the YHGY loop in E. coli methionine aminopeptidase, and likely in other bacterial methionine aminopeptidases, enables the enzyme active pocket to accommodate inhibitors of differing size. The differences in this adaptable loop between the bacterial and human methionine aminopeptidases is a structural feature that can be exploited to design inhibitors of bacterial methionine aminopeptidases as therapeutic agents with minimal inhibition of the corresponding human enzymes.

Show MeSH