6ov7
CFTR Associated Ligand (CAL) PDZ domain bound to peptide kCAL01
Structural highlights
DiseaseGOPC_HUMAN Note=A chromosomal aberration involving GOPC is found in a glioblastoma multiforme sample. An intra-chromosomal deletion del(6)(q21q21) is responsible for the formation of GOPC-ROS1 chimeric protein which has a constitutive receptor tyrosine kinase activity.[1] FunctionGOPC_HUMAN Plays a role in intracellular protein trafficking and degradation. May regulate CFTR chloride currents and acid-induced ASIC3 currents by modulating cell surface expression of both channels. May also regulate the intracellular trafficking of the ADR1B receptor. May play a role in autophagy. Overexpression results in CFTR intracellular retention and degradation in the lysosomes.[2] [3] [4] Publication Abstract from PubMedThe CFTR-associated ligand PDZ domain (CALP) binds to the cystic fibrosis transmembrane conductance regulator (CFTR) and mediates lysosomal degradation of mature CFTR. Inhibition of this interaction has been explored as a therapeutic avenue for cystic fibrosis. Previously, we reported the ensemble-based computational design of a novel peptide inhibitor of CALP, which resulted in the most binding-efficient inhibitor to date. This inhibitor, kCAL01, was designed using OSPREY and evinced significant biological activity in in vitro cell-based assays. Here, we report a crystal structure of kCAL01 bound to CALP and compare structural features against iCAL36, a previously developed inhibitor of CALP. We compute side-chain energy landscapes for each structure to not only enable approximation of binding thermodynamics, but also reveal ensemble features that contribute to the comparatively efficient binding of kCAL01. Finally, we compare the previously reported design ensemble for kCAL01 vs. the new crystal structure and show that, despite small differences between the design model and crystal structure, significant biophysical features that enhance inhibitor binding are captured in the design ensemble. This suggests not only that ensemble-based design captured thermodynamically significant features observed in vitro, but also that a design eschewing ensembles would miss the kCAL01 sequence entirely. Computational Analysis of Energy Landscapes Reveals Dynamic Features that Contribute to Binding of Inhibitors to CFTR-Associated Ligand.,Holt GT, Jou JD, Gill NP, Lowegard AU, Martin JW, Madden DR, Donald BR J Phys Chem B. 2019 Nov 7. doi: 10.1021/acs.jpcb.9b07278. PMID:31697075[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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