Predicting function from structure: examples of the serine protease inhibitor canonical loop conformation found in extracellular proteins |
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| Affiliation: | 1. Department of Biochemistry and Molecular Biology, University College, Gower Street, London WC1E 6BT, UK;2. Bioinformatics Research Group, SmithKline Beecham Pharmaceuticals Research and Development, New Frontiers Science Park (North), Harlow, Essex CM19 5AW, UK;1. Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh 453552, India;2. Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India;1. Green Catalysis Center and College of Chemistry, Zhengzhou University, Zhengzhou 450001, Henan, PR China;2. School of Chemistry, Xi''an Jiaotong University, Xi''an, Shaanxi 710049, China;3. Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, PR China;4. Functional Inorganic Materials Lab (FIML), Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India;1. Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India;2. Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India;1. Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;2. Department of Biochemistry, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, China;3. Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China |
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| Abstract: | The prediction of protein function from structure is becoming of growing importance in the age of structural genomics. We have focused on the problem of identifying sites of potential serine protease inhibitor interactions on the surface of proteins of known structure. Given that there is no sequence conservation within canonical loops from different inhibitor families we first compare representative loops to all fragments of equal length among proteins of known structure by calculating main-chain RMS deviation. Fragments with RMS deviation below a certain threshold (hits) are removed if residues have solvent accessibilities appreciably lower than those observed in the search structure. These remaining hits are further filtered to remove those occurring largely within secondary structure elements. Likely functional significance is restricted further by considering only extracellular protein domains. Also a test is performed to see if the loop can dock into the binding site of the serine protease trypsin without unacceptable steric clashes. By comparing different canonical loop structures to the protein structure database we show that the method was able to detect previously known inhibitors. In addition, we discuss potentially new canonical loop structures found in secreted hydrolases, toxins, viral proteins, cytokines and other proteins. We discuss the possible functional significance of several of the examples found. |
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