7opb
IL7R in complex with an antagonist
Structural highlights
DiseaseIL7RA_HUMAN Defects in IL7R are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (T(-)B(+)NK(+) SCID) [MIM:608971. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.[1] [:][2] [3] [4] Genetic variations in IL7R are a cause of susceptibility to multiple sclerosis type 3 (MS3) [MIM:612595. A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheat, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. Note=A polymorphism at position 244 strongly influences susceptibility to multiple sclerosis. Overtransmission of the major 'C' allele coding for Thr-244 is detected in offspring affected with multiple sclerosis. In vitro analysis of transcripts from minigenes containing either 'C' allele (Thr-244) or 'T' allele (Ile-244) shows that the 'C' allele results in an approximately two-fold increase in the skipping of exon 6, leading to increased production of a soluble form of IL7R. Thus, the multiple sclerosis associated 'C' risk allele of IL7R would probably decrease membrane-bound expression of IL7R. As this risk allele is common in the general population, some additional triggers are probably required for the development and progression of MS.[5] FunctionIL7RA_HUMAN Receptor for interleukin-7. Also acts as a receptor for thymic stromal lymphopoietin (TSLP). Publication Abstract from PubMedThe design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge(1-5). We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and following experimental optimization bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications. Design of protein binding proteins from target structure alone.,Cao L, Coventry B, Goreshnik I, Huang B, Park JS, Jude KM, Markovic I, Kadam RU, Verschueren KHG, Verstraete K, Walsh STR, Bennett N, Phal A, Yang A, Kozodoy L, DeWitt M, Picton L, Miller L, Strauch EM, DeBouver ND, Pires A, Bera AK, Halabiya S, Hammerson B, Yang W, Bernard S, Stewart L, Wilson IA, Ruohola-Baker H, Schlessinger J, Lee S, Savvides SN, Garcia KC, Baker D Nature. 2022 Mar 24. pii: 10.1038/s41586-022-04654-9. doi:, 10.1038/s41586-022-04654-9. PMID:35332283[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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