Shrilakshmi Sheshagiri Rao, Shankar V Kundapura, Debayan Dey, Chandrasekaran Palaniappan, Kanagaraj Sekar, Ananda Kulal, Udupi A Ramagopal
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引用次数: 0
Abstract
The insulin superfamily proteins (ISPs), in particular, insulin, IGFs and relaxin proteins are key modulators of animal physiology. They are known to have evolved from the same ancestral gene and have diverged into proteins with varied sequences and distinct functions, but maintain a similar structural architecture stabilized by highly conserved disulphide bridges. The recent surge of sequence data and the structures of these proteins prompted a need for a comprehensive analysis, which connects the evolution of these sequences (427 sequences) in the light of available functional and structural information including representative complex structures of ISPs with their cognate receptors. This study reveals (a) unusually high sequence conservation of IGFs (>90 % conservation in 184 sequences) and provides a possible structure-based rationale for such high sequence conservation; (b) provides an updated definition of the receptor-binding signature motif of the functionally diverse relaxin family members (c) provides a probable non-canonical C-peptide cleavage site in a few insulin sequences. The high conservation of IGFs appears to represent a classic case of resistance to sequence diversity exerted by physiologically important interactions with multiple partners. We also propose a probable mechanism for C-peptide cleavage in a few distinct insulin sequences and redefine the receptor-binding signature motif of the relaxin family. Lastly, we provide a basis for minimally modified insulin mutants with potential therapeutic application, inspired by concomitant changes observed in other insulin superfamily protein members supported by molecular dynamics simulation.
期刊介绍:
Molecular Informatics is a peer-reviewed, international forum for publication of high-quality, interdisciplinary research on all molecular aspects of bio/cheminformatics and computer-assisted molecular design. Molecular Informatics succeeded QSAR & Combinatorial Science in 2010.
Molecular Informatics presents methodological innovations that will lead to a deeper understanding of ligand-receptor interactions, macromolecular complexes, molecular networks, design concepts and processes that demonstrate how ideas and design concepts lead to molecules with a desired structure or function, preferably including experimental validation.
The journal''s scope includes but is not limited to the fields of drug discovery and chemical biology, protein and nucleic acid engineering and design, the design of nanomolecular structures, strategies for modeling of macromolecular assemblies, molecular networks and systems, pharmaco- and chemogenomics, computer-assisted screening strategies, as well as novel technologies for the de novo design of biologically active molecules. As a unique feature Molecular Informatics publishes so-called "Methods Corner" review-type articles which feature important technological concepts and advances within the scope of the journal.