4hop

Crystal structure of the computationally designed NNOS-Syntrophin complex

spinqualitylabelsall models 4hop, resolution 2.29Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4hop is a 6 chain structure with sequence from Mus musculus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SNTA1_MOUSE Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins. May link various receptors to the actin cytoskeleton and the extracellular matrix via the dystrophin glycoprotein complex. Plays an important role in synapse formation and in the organization of UTRN and acetylcholine receptors at the neuromuscular synapse. Binds to phosphatidylinositol 4,5-bisphosphate. Publication Abstract from PubMed Reengineering protein-protein recognition is an important route to dissecting and controlling complex interaction networks. Experimental approaches have used the strategy of "second-site suppressors," where a functional interaction is inferred between two proteins if a mutation in one protein can be compensated by a mutation in the second. Mimicking this strategy, computational design has been applied successfully to change protein recognition specificity by predicting such sets of compensatory mutations in protein-protein interfaces. To extend this approach, it would be advantageous to be able to "transplant" existing engineered and experimentally validated specificity changes to other homologous protein-protein complexes. Here, we test this strategy by designing a pair of mutations that modulates peptide recognition specificity in the Syntrophin PDZ domain, confirming the designed interaction biochemically and structurally, and then transplanting the mutations into the context of five related PDZ domain-peptide complexes. We find a wide range of energetic effects of identical mutations in structurally similar positions, revealing a dramatic context dependence (epistasis) of designed mutations in homologous protein-protein interactions. To better understand the structural basis of this context dependence, we apply a structure-based computational model that recapitulates these energetic effects and we use this model to make and validate forward predictions. Although the context dependence of these mutations is captured by computational predictions, our results both highlight the considerable difficulties in designing protein-protein interactions and provide challenging benchmark cases for the development of improved protein modeling and design methods that accurately account for the context. Quantification of the transferability of a designed protein specificity switch reveals extensive epistasis in molecular recognition.,Melero C, Ollikainen N, Harwood I, Karpiak J, Kortemme T Proc Natl Acad Sci U S A. 2014 Oct 13. pii: 201410624. PMID:25313039 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Nitric Oxide Synthase 3D structures Syntrophin

Proteopedia Page Contributors and Editors (what is this?)

OCA