Crystal Structure of GRIP1 PDZ6-Peptide Complex Reveals the Structural Basis for Class II PDZ Target Recognition and PDZ Domain-mediated Multimerization

Young Jun Im; Seong Ho Park; Seong-Hwan Rho; Jun Hyuck Lee; Gil Bu Kang; Morgan Sheng; Eunjoon Kim; Soo Hyun Eom

doi:10.1074/jbc.m212263200

Crystal Structure of GRIP1 PDZ6-Peptide Complex Reveals the Structural Basis for Class II PDZ Target Recognition and PDZ Domain-mediated Multimerization

Journal of Biological Chemistry ◽

10.1074/jbc.m212263200 ◽

2002 ◽

Vol 278 (10) ◽

pp. 8501-8507 ◽

Cited By ~ 64

Author(s):

Young Jun Im ◽

Seong Ho Park ◽

Seong-Hwan Rho ◽

Jun Hyuck Lee ◽

Gil Bu Kang ◽

...

Keyword(s):

Crystal Structure ◽

Target Recognition ◽

Pdz Domain ◽

Class Ii ◽

Structural Basis ◽

Peptide Complex

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Crystal structure of the hCASK PDZ domain reveals the structural basis of class II PDZ domain target recognition

Natural Structural Biology ◽

10.1038/nsb0498-317 ◽

1998 ◽

Vol 5 (4) ◽

pp. 317-325 ◽

Cited By ~ 139

Author(s):

Danette L. Daniels ◽

Alexandra R. Cohen ◽

James M. Anderson ◽

Axel T. Brünger

Keyword(s):

Crystal Structure ◽

Target Recognition ◽

Pdz Domain ◽

Class Ii ◽

Structural Basis

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Computational Analysis of Energy Landscapes Reveals Dynamic Features that Contribute to Binding of Inhibitors to CFTR-Associated Ligand

10.1101/720342 ◽

2019 ◽

Author(s):

Graham T. Holt ◽

Jonathan D. Jou ◽

Nicholas P. Gill ◽

Anna U. Lowegard ◽

Jeffrey W. Martin ◽

...

Keyword(s):

Crystal Structure ◽

Pdz Domain ◽

Computational Design ◽

Structural Features ◽

Structural Basis ◽

Conformational Ensemble ◽

Energy Landscapes ◽

Dynamic Features ◽

Design Algorithm

AbstractPDZ domains are small protein-binding domains that interact with short, mostly C-terminal peptides and play important roles in cellular signaling and the trafficking and localization of ion channels. The CFTR-associated ligand PDZ domain (CALP) binds to the cystic fibro-sis transmembrane conductance regulator (CFTR) and mediates degradation of mature CFTR through lysosomal pathways. Inhibition of the CALP:CFTR interaction has been explored as a potential therapeutic avenue for cystic fibrosis (CF).1 Previously, we reported2 the ensemble-based computational design of a novel 6-residue peptide inhibitor of CALP, which resulted in the most binding-efficient inhibitor of CALP to date. This inhibitor, kCAL01, was designed using OSPREY3 and displayed significant biological activity in in vitro cell-based assays. Here, we report a crystal structure of kCAL01 bound to CALP (PDB ID: 6OV7). To elucidate the structural basis for the enhanced binding efficiency of kCAL01, we compare this structure to that of a previously developed inhibitor of CALP, iCAL36 (PDB ID: 4E34). In addition to per-forming traditional structural analysis, we compute the side-chain energy landscapes for each structure using the recently developed MARK* partition function approximation algorithm.4 Analysis of these energy landscapes not only enables approximation of binding thermodynamics for these structural models of CALP:inhibitor binding, but also foregrounds important structural features and reveals dynamic features, both of which contribute to the comparatively efficient binding of kCAL01. The investigation of energy landscapes complements traditional analysis of the few low-energy conformations found in crystal structures, and provides information about the entire conformational ensemble that is accessible to a protein structure model. Finally, we compare the previously reported NMR-based design model ensemble for kCAL01 vs. the new crystal structure and show that, despite the notable differences between the CALP NMR model and crystal structure, many significant features are successfully 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 algorithm eschewing ensembles would likely miss the kCAL01 sequence entirely.Graphical TOC Entry

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