Kortemme, Tanja - University of California, San Francisco - Department of Chemistry and Chemical Biology

研究领域

We are interested in how biological molecules communicate with each other, and how this communication encodes the processing of information. How do biomolecules recognize one another, and how do their interactions transduce signals? How do molecules build up "modules" that act as "adaptors", "switches" and feedback-loops? How are modules wired together into the networks responsible for regulation and decision processes observed in biology? Computationally, we have developed a simple physical energy function for the prediction and design of protein-protein interactions, at the atomic level. Experimentally, we have applied this model to the computational redesign of a protein interface and have created an artificial DNA binding protein with new specificity. More recently, we have developed a computational strategy for the redesign of protein complexes to generate new pairs of interacting proteins. We are now applying and extending our computational model at different "resolution", ranging from details of atom-atom interactions to cellular communication networks. We are aiming to develop more accurate methods to model the structural details of molecular interactions. Can new interactions and modules with defined properties be engineered? Ultimately we would like to apply computational and experimental methods to better understand how cellular processes are regulated by molecular communication.

近期论文

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Ollikainen, N, Kortemme, T. Computational Protein Design Quantifies Structural Constraints on Amino Acid Covariation. PLoS Comput Biol 9(11):e1003313. doi: 10.1371/journal.pcbi.1003313 Hoersch, D, Roh, S, Chiu, W, Kortemme, T. Reprogramming an ATP-driven protein machine into a light-gated nanocage. Nat Nano 8(12):928-32. doi: 10.1038/nnano.2013.242 Ritterson, RS, Kuchenbecker, KM, Michalik, M, Kortemme, T. Design of a Photoswitchable Cadherin. J Am Chem Soc 135(34):12516-9. Stein, A, Kortemme, T. Improvements to Robotics-Inspired Conformational Sampling in Rosetta. PLoS ONE 8(5):e63090. doi: 10.1371/journal.pone.0063090 Lyskov, S, Chou, F, Ó Conchúir, S, Der, BS, Drew, K, Kuroda, D, Xu, J, Weitzner, BD, Renfrew, PD, Sripakdeevong, P, Borgo, B, Havranek, JJ, Kuhlman, B, Kortemme, T, Bonneau, R, Gray, JJ, Das, R. Serverification of Molecular Modeling Applications: The Rosetta Online Server That Includes Everyone (ROSIE). PLoS ONE 8(5):e63906. doi: 10.1371/journal.pone.0063906 Smith, CA, Shi, CA, Chroust, MK, Bliska, TE, Kelly, MJS, Jacobson, MP, Kortemme, T. Design of a Phosphorylatable PDZ Domain with Peptide-Specific Affinity Changes. Structure 21(1):54-64. doi: 10.1016/j.str.2012.10.007 Ollikainen, N, Smith, CA, Fraser, JS, Kortemme, T. Chapter Four - Flexible Backbone Sampling Methods to Model and Design Protein Alternative Conformations in Methods in Enzymology Volume 523 (Methods in Protein Design):61-85. doi: 10.1016/B978-0-12-394292-0.00004-7 Leaver-Fay, A, O'Meara, MJ, Tyka, M, Jacak, R, Song, Y, Kellogg, EH, Thompson, J, Davis, IW, Pache, RA, Lyskov, S, Gray, JJ, Kortemme, T, Richardson, JS, Havranek, JJ, Snoeyink, J, Baker, D, Kuhlman, B. Chapter Six - Scientific Benchmarks for Guiding Macromolecular Energy Function Improvement in Methods in Enzymology Volume 523 (Methods in Protein Design):109-43. doi: 10.1016/B978-0-12-394292-0.00006-0 Humphris-Narayanan, EL, Akiva, E, Varela, R, Ó Conchúir, S, Kortemme, T. Prediction of Mutational Tolerance in HIV-1 Protease and Reverse Transcriptase Using Flexible Backbone Protein Design. PLoS Comput Biol 8(8):e1002639. doi: 10.1371/journal.pcbi.1002639 Eames, M, Kortemme, T. Cost-Benefit Tradeoffs in Engineered lac Operons. Science 336(6083):911-5. doi: 10.1126/science.1219083 [free download] Kapp, GT, Liu, S, Stein, A, Wong, DT, Reményi, A, Yeh, BJ, Fraser, JS, Taunton, J, Lim, WA, Kortemme, T. Control of protein signaling using a computationally designed GTPase/GEF orthogonal pair. Proc Natl Acad Sci U S A :5277-82. doi: 10.1073/pnas.1114487109 Jager, S, Cimermancic, P, Gulbahce, N, Johnson, JR, McGovern, KE, Clarke, SC, Shales, M, Mercenne, G, Pache, L, Li, K, Hernandez, H, Jang, GM, Roth, SL, Akiva, E, Marlett, J, Stephens, M, D/'Orso, I, Fernandes, J, Fahey, M, Mahon, C, O/'Donoghue, AJ, Todorovic, A, Morris, JH, Maltby, DA, Alber, T, Cagney, G, Bushman, FD, Young, JA, Chanda, SK, Sundquist, WI, Kortemme, T, Hernandez, RD, Craik, CS, Burlingame, AL, Sali, A, Frankel, AD, Krogan, NJ. Global landscape of HIV-human protein complexes. Nature 481(7381):365-70. doi: 10.1038/nature10719 Chao, LH, Stratton, MM, Lee, I, Rosenberg, OS, Levitz, J, Mandell, DJ, Kortemme, T, Groves, JT, Schulman, H, Kuriyan, J. A Mechanism for Tunable Autoinhibition in the Structure of a Human Ca2+/Calmodulin- Dependent Kinase II Holoenzyme. Cell 146(5):732-45. doi: 10.1016/j.cell.2011.07.038 Smith, CA, Kortemme, T. Predicting the Tolerated Sequences for Proteins and Protein Interfaces Using RosettaBackrub Flexible Backbone Design. PLoS ONE 6(7):e20451. doi: 10.1371/journal.pone.0020451 Babor, M, Mandell, DJ, Kortemme, T. Assessment of flexible backbone protein design methods for sequence library prediction in the therapeutic antibody Herceptin–HER2 interface. Protein Sci 20(6):1082-9. doi: 10.1002/pro.632 Leaver-Fay, A, Tyka, M, Lewis, SM, Lange, OF, Thompson, J, Jacak, R, Kaufman, KW, Renfrew, PD, Smith, CA, Sheffler, W, Davis, IW, Cooper, S, Treuille, A, Mandell, DJ, Richter, F, Ban, YA, Fleishman, SJ, Corn, JE, Kim, DE, Lyskov, S, Berrondo, M, Mentzer, S, Popović, Z, Havranek, JJ, Karanicolas, J, Das, R, Meiler, J, Kortemme, T, Gray, JJ, Kuhlman, B, Baker, D, Bradley, P. Chapter nineteen - Rosetta3: An Object-Oriented Software Suite for the Simulation and Design of Macromolecules in Methods in Enzymology Volume 487 (Computer Methods, Part C):545-74. doi: 10.1016/B978-0-12-381270-4.00019-6 Moon, TS, Clarke, EJ, Groban, ES, Tamsir, A, Clark, RM, Eames, M, Kortemme, T, Voigt, CA. Construction of a Genetic Multiplexer to Toggle between Chemosensory Pathways in Escherichia coli. J Mol Biol 406(2):215-27. doi: 10.1016/j.jmb.2010.12.019 Smith, CA, Kortemme, T. Structure-Based Prediction of the Peptide Sequence Space Recognized by Natural and Synthetic PDZ Domains. J Mol Biol 402(2):460-74. doi: 10.1016/j.jmb.2010.07.032 Lauffer, BEL, Melero, C, Temkin, P, Lei, C, Hong, W, Kortemme, T, von Zastrow, M. SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane. J Cell Biol 190(4):565-74. doi: 10.1083/jcb.201004060 Lauck, F, Smith, CA, Friedland, GD, Humphris, EL, Kortemme, T. RosettaBackrub—a web server for flexible backbone protein structure modeling and design. Nucleic Acids Res 38(suppl 2):W569-75. doi: 10.1093/nar/gkq369