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Target selection and annotation for the structural genomics of the amidohydrolase and enolase superfamilies |
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| Authors: | Ursula Pieper Ranyee Chiang Jennifer J Seffernick Shoshana D Brown Margaret E Glasner Libusha Kelly Narayanan Eswar J Michael Sauder Jeffrey B Bonanno Subramanyam Swaminathan Stephen K Burley Xiaojing Zheng Mark R Chance Steven C Almo John A Gerlt Frank M Raushel Matthew P Jacobson Patricia C Babbitt Andrej Sali | ||
| Institution: | 1. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California at San Francisco, Byers Hall at Mission Bay, Office 501-32, 1700 4th Street, San Francisco, CA, 94158, USA 2. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California at San Francisco, Byers Hall at Mission Bay, Office 501, 1700 4th Street, San Francisco, CA, 94158, USA 3. Department of Biopharmaceutical Sciences, California Institute for Quantitative Biosciences, University of California at San Francisco, Byers Hall at Mission Bay, Office 501C, 1700 4th Street, San Francisco, CA, 94158, USA 4. SGX Pharmaceuticals Inc, 10505 Roselle Street, San Diego, CA, 92121, USA 5. Departments of Biochemistry and Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA 6. Biology Department, Brookhaven National Laboratory, Upton, NY, 11973, USA 7. Case Center for Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, OH, 44106, USA 8. Departments of Biochemistry and Chemistry, University of Illinois, Urbana, IL, 61801, USA 9. Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, TX, 77842-3012, USA 10. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California at San Francisco, 600 16th St., Box 2240, Genentech Hall at Mission Bay, Room N472C, San Francisco, CA, 94158-2517, USA 11. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California at San Francisco, Byers Hall at Mission Bay, Office 508E, 1700 4th Street, San Francisco, CA, 94158, USA 12. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California at San Francisco, Byers Hall at Mission Bay, Office 503B, 1700 4th Street, San Francisco, CA, 94158, USA |
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| Abstract: | To study the substrate specificity of enzymes, we use the amidohydrolase and enolase superfamilies as model systems; members
of these superfamilies share a common TIM barrel fold and catalyze a wide range of chemical reactions. Here, we describe a
collaboration between the Enzyme Specificity Consortium (ENSPEC) and the New York SGX Research Center for Structural Genomics
(NYSGXRC) that aims to maximize the structural coverage of the amidohydrolase and enolase superfamilies. Using sequence- and
structure-based protein comparisons, we first selected 535 target proteins from a variety of genomes for high-throughput structure
determination by X-ray crystallography; 63 of these targets were not previously annotated as superfamily members. To date,
20 unique amidohydrolase and 41 unique enolase structures have been determined, increasing the fraction of sequences in the
two superfamilies that can be modeled based on at least 30% sequence identity from 45% to 73%. We present case studies of
proteins related to uronate isomerase (an amidohydrolase superfamily member) and mandelate racemase (an enolase superfamily
member), to illustrate how this structure-focused approach can be used to generate hypotheses about sequence–structure–function
relationships.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
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| Keywords: | Amidohydrolase and enolase superfamilies Structural genomics Structure annotation Target selection | ||
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