Abstract
The accurate structural modeling of B- and T-cell receptors is fundamental to gain a detailed insight in the mechanisms underlying immunity and in developing new drugs and therapies. The LYRA (LYmphocyte Receptor Automated modeling) web server (http://www.cbs.dtu.dk/services/LYRA/) implements a complete and automated method for building of B- and T-cell receptor structural models starting from their amino acid sequence alone. The webserver is freely available and easy to use for non-specialists. Upon submission, LYRA automatically generates alignments using ad hoc profiles, predicts the structural class of each hypervariable loop, selects the best templates in an automatic fashion, and provides within minutes a complete 3D model that can be downloaded or inspected online. Experienced users can manually select or exclude template structures according to case specific information. LYRA is based on the canonical structure method, that in the last 30 years has been successfully used to generate antibody models of high accuracy, and in our benchmarks this approach proves to achieve similarly good results on TCR modeling, with a benchmarked average RMSD accuracy of 1.29 and 1.48 Å for B- and T-cell receptors, respectively. To the best of our knowledge, LYRA is the first automated server for the prediction of TCR structure.
Highlights
IntroductionThe immune system has the ability to target and fight with extreme efficacy and specificity dangerous molecules of either exogenous (pathogens, toxins) or self-origin (tumors, metabolic by-products)
The immune system has the ability to target and fight with extreme efficacy and specificity dangerous molecules of either exogenous or self-origin
In order to test the accuracy of LYRA, we applied a leave-one-out procedure to all the paired T cell receptors (TCR) and B cell receptor (BCR) molecules in our template database
Summary
The immune system has the ability to target and fight with extreme efficacy and specificity dangerous molecules of either exogenous (pathogens, toxins) or self-origin (tumors, metabolic by-products). Even though the diversity of the antibodies produced in a single person is larger than that of all other human proteins altogether [6], we can predict their structure with extreme accuracy [7,8] This exceptional ability derives from a fundamental discovery that Chothia and Lesk made 30 years ago [9,10,11]: T- and B-cell receptors have a very large sequence variability, especially in their antigen-binding site (ABS), this does not have a comparable effect on their main chain conformation that is very conserved.
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