scholarly journals A functional NMR for membrane proteins: dynamics, ligand binding, and allosteric modulation

2016 ◽  
Vol 25 (5) ◽  
pp. 959-973 ◽  
Author(s):  
Kirill Oxenoid ◽  
James J. Chou
Keyword(s):  
Membrane Proteins ◽  
Ligand Binding ◽  
Allosteric Modulation

scholarly journals Allostery revealed within lipid binding events to membrane proteins

2018 ◽  
Vol 115 (12) ◽  
pp. 2976-2981 ◽  
Author(s):  
John W. Patrick ◽  
Christopher D. Boone ◽  
Wen Liu ◽  
Gloria M. Conover ◽  
Yang Liu ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Protein Interactions ◽  
Biological Membrane ◽  
Binding Constants ◽  
Native Mass Spectrometry ◽  
Specific Protein ◽  
Lipid Binding ◽  
Allosteric Modulation ◽  
Lipid Species ◽  
Specific Lipid

Membrane proteins interact with a myriad of lipid species in the biological membrane, leading to a bewildering number of possible protein−lipid assemblies. Despite this inherent complexity, the identification of specific protein−lipid interactions and the crucial role of lipids in the folding, structure, and function of membrane proteins is emerging from an increasing number of reports. Fundamental questions remain, however, regarding the ability of specific lipid binding events to membrane proteins to alter remote binding sites for lipids of a different type, a property referred to as allostery [Monod J, Wyman J, Changeux JP (1965)J Mol Biol12:88–118]. Here, we use native mass spectrometry to determine the allosteric nature of heterogeneous lipid binding events to membrane proteins. We monitored individual lipid binding events to the ammonia channel (AmtB) fromEscherichia coli, enabling determination of their equilibrium binding constants. We found that different lipid pairs display a range of allosteric modulation. In particular, the binding of phosphatidylethanolamine and cardiolipin-like molecules to AmtB exhibited the largest degree of allosteric modulation, inspiring us to determine the cocrystal structure of AmtB in this lipid environment. The 2.45-Å resolution structure reveals a cardiolipin-like molecule bound to each subunit of the trimeric complex. Mutation of a single residue in AmtB abolishes the positive allosteric modulation observed for binding phosphatidylethanolamine and cardiolipin-like molecules. Our results demonstrate that specific lipid−protein interactions can act as allosteric modulators for the binding of different lipid types to integral membrane proteins.

scholarly journals Hidden electrostatic basis of dynamic allostery in a PDZ domain

2017 ◽  
Vol 114 (29) ◽  
pp. E5825-E5834 ◽  
Author(s):  
Amit Kumawat ◽  
Suman Chakrabarty
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Electrostatic Interactions ◽  
Pdz Domain ◽  
Allosteric Modulation ◽  
Side Chain ◽  
Salt Bridges ◽  
Population Shift ◽  
Domain Protein ◽  
Dynamics Simulations

Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters. There is a significant population shift in the hydrogen-bonded network and salt bridges involving side chains on ligand binding. The ligand creates a local energetic perturbation that propagates in the form of dominolike changes in interresidue interaction pattern. There are significant changes in the nature of specific interactions (nonpolar/polar) between interresidue contacts and accompanied side-chain reorientations that drive the major redistribution of energy. Interestingly, this internal redistribution and rewiring of side-chain interactions led to large cancellations resulting in small change in the overall enthalpy of the protein, thus making it difficult to detect experimentally. In contrast to the prevailing focus on the entropic or dynamic effects, we show that the internal redistribution and population shift in specific electrostatic interactions drive the allosteric modulation in the PDZ3 domain protein.

scholarly journals Use of NMR Saturation Transfer Difference Spectroscopy to Study Ligand Binding to Membrane Proteins

2012 ◽  
pp. 47-63 ◽  
Author(s):  
Rani Parvathy Venkitakrishnan ◽  
Outhiriaradjou Benard ◽  
Marianna Max ◽  
John L. Markley ◽  
Fariba M. Assadi-Porter
Keyword(s):  
Membrane Proteins ◽  
Ligand Binding ◽  
Difference Spectroscopy ◽  
Saturation Transfer ◽  
Saturation Transfer Difference

scholarly journals Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures

2020 ◽  
Vol 21 (21) ◽  
pp. 8348
Author(s):  
Dániel Dudola ◽  
Anett Hinsenkamp ◽  
Zoltán Gáspári
Keyword(s):  
Ligand Binding ◽  
General Feature ◽  
Allosteric Modulation ◽  
Side Chain ◽  
Ligand Specificity ◽  
Structural Rearrangements ◽  
Pdz Domains ◽  
Postsynaptic Protein ◽  
Conformational Diversity ◽  
Structural Ensembles

PDZ domains are abundant interaction hubs found in a number of different proteins and they exhibit characteristic differences in their structure and ligand specificity. Their internal dynamics have been proposed to contribute to their biological activity via changes in conformational entropy upon ligand binding and allosteric modulation. Here we investigate dynamic structural ensembles of PDZ3 of the postsynaptic protein PSD-95, calculated based on previously published backbone and side-chain S2 order parameters. We show that there are distinct but interdependent structural rearrangements in PDZ3 upon ligand binding and the presence of the intramolecular allosteric modulator helix α3. We have also compared these rearrangements in PDZ1-2 of PSD-95 and the conformational diversity of an extended set of PDZ domains available in the PDB database. We conclude that although the opening-closing rearrangement, occurring upon ligand binding, is likely a general feature for all PDZ domains, the conformer redistribution upon ligand binding along this mode is domain-dependent. Our findings suggest that the structural and functional diversity of PDZ domains is accompanied by a diversity of internal motional modes and their interdependence.

Seasonal patterns in platelet ligand binding are related to membrane proteins

1996 ◽  
Vol 39 (6) ◽  
pp. 430-435 ◽  
Author(s):  
Edward M. DeMet ◽  
Aleksandra Chicz-Demet
Keyword(s):  
Membrane Proteins ◽  
Ligand Binding ◽  
Seasonal Patterns
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