4NXR

Crystal Structure of T-cell Lymphoma Invasion and Metastasis-1 PDZ Domain Quadruple Mutant (QM) in Complex With Neurexin-1 Peptide

Summary for 4NXR

• Entry DOI: 10.2210/pdb4nxr/pdb
• Related: 3KZD 3KZE 4GVC 4GVD 4NXP 4NXQ
• Descriptor: T-lymphoma invasion and metastasis-inducing protein 1, Neurexin-2-beta Peptide, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: beta barrel fold protein, pdz domain, peptide binding, specificity mutant, scaffold signaling protein for cell adhesion and cell junction, signaling domain, signaling protein-peptide complex, signaling protein/peptide
• Biological source: Homo sapiens (human); More
• Cellular location: Cell junction: Q13009; Membrane ; Single-pass type I membrane protein : P58401
• Total number of polymer chains: 2
• Total formula weight: 11742.17

Authors

Liu, X.,Speckhard, D.C.,Shepherd, T.R.,Hengel, S.R.,Fuentes, E.J. (deposition date: 2013-12-09, release date: 2015-05-13, Last modification date: 2023-09-20)

Primary citation

Liu, X.,Speckhard, D.C.,Shepherd, T.R.,Sun, Y.J.,Hengel, S.R.,Yu, L.,Fowler, C.A.,Gakhar, L.,Fuentes, E.J.
Distinct Roles for Conformational Dynamics in Protein-Ligand Interactions.
Structure, 24:2053-2066, 2016

PubMed Abstract: Conformational dynamics has an established role in enzyme catalysis, but its contribution to ligand binding and specificity is largely unexplored. Here we used the Tiam1 PDZ domain and an engineered variant (QM PDZ) with broadened specificity to investigate the role of structure and conformational dynamics in molecular recognition. Crystal structures of the QM PDZ domain both free and bound to ligands showed structural features central to binding (enthalpy), while nuclear-magnetic-resonance-based methyl relaxation experiments and isothermal titration calorimetry revealed that conformational entropy contributes to affinity. In addition to motions relevant to thermodynamics, slower microsecond to millisecond switching was prevalent in the QM PDZ ligand-binding site consistent with a role in ligand specificity. Our data indicate that conformational dynamics plays distinct and fundamental roles in tuning the affinity (conformational entropy) and specificity (excited-state conformations) of molecular interactions. More broadly, our results have important implications for the evolution, regulation, and design of protein-ligand interactions.

PubMed: 27998539
DOI: 10.1016/j.str.2016.08.019

Experimental method

X-RAY DIFFRACTION (1.9 Å)