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Advances in NMR Methods to Identify Allosteric Sites and Allosteric Ligands

  • Hazem Abdelkarim
  • Ben Hitchinson
  • Avik Banerjee
  • Vadim GaponenkoEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1163)

Abstract

NMR allows assessment of protein structure in solution. Unlike conventional X-ray crystallography that provides snapshots of protein conformations, all conformational states are simultaneously accessible to analysis by NMR. This is a significant advantage for discovery and characterization of allosteric effects. These effects are observed when binding at one site of the protein affects another distinct site through conformational transitions. Allosteric regulation of proteins has been observed in multiple physiological processes in health and disease, providing an opportunity for the development of allosteric inhibitors. These compounds do not directly interact with the orthosteric site of the protein but influence its structure and function. In this book chapter, we provide an overview on how NMR methods are utilized to identify allosteric sites and to discover novel inhibitors, highlighting examples from the field. We also describe how NMR has contributed to understanding of allosteric mechanisms and propose that it is likely to play an important role in clarification and further development of key concepts of allostery.

Keywords

NMR Allosteric ligands Allosteric sites NMR methods 

Abbreviations

14–3-3

Conserved regulatory/adaptive proteins

19F NMR

Fluorine NMR spectroscopy

Å

Angstroms

AMP

Adenosine-5-monophosphate

CHESCA

Chemical shift covariance analysis

CORCEMA-ST

Conformational exchange matrix analysis of saturation transfer

CPMG

Carr-Purcell-Meiboom-Gill

DHF

Dihydrofolate

DHFR

Dihydrofolate reductase

DHPS

Dihydropteroate synthase

DNA

Deoxyribonucleic acid

Eg5

Plus-end-directed kinesin-related protein

EPAC

Exchange protein directly activated by cAMP

F

Fluorine

FAXS

Fluorine chemical shift anisotropy and exchange for screening

GDP

Guanosine diphosphate

GMPPCP

β, γ-Methyleneguanosine triphosphate

GPCRs

G-protein-coupled receptors

GTP

Guanosine triphosphate

H

Hydrogen

HBGAs

Histo-blood antigens

HSQC/HMQC

Heteronuclear single/multiple quantum coherence/correlation

ITK

Interleukin-2-inducible T-cell kinase

KNF

Koshland, Némethy, and Filmer

MD

Molecular dynamics

MerR

The bacterial mercury resistance

MWC

Monod-Wyman-Changeux

N

Nitrogen

NMR

Nuclear magnetic resonance

NOEs

Nuclear Overhauser effects

pABA

p-Aminobenzoic acid

PCSs

Pseudocontact shifts

PDK1

Phosphoinositide-dependent kinase-1

PIF

PDK1 interacting fragment

PREs

Paramagnetic relaxation enhancements

R1

15N spin-lattice relaxation experiments

R2

Spin-spin relaxation experiments

RDCs

Residual dipolar couplings

RNA

Ribonucleic acid

SOS

Son of sevenless

STD-NMR

Saturation transfer difference

TET

2,2,2-Trifluoroethanethiol

THF

Tetrahydrofolate

TROSY

Transverse relaxation optimized spectroscopy

VLPs

Norovirus virus-like particles

WaterLOGSY

Water ligand observed via gradient spectroscopy

Notes

Acknowledgments

This work was funded by the National Institutes of Health (NIH)–National Cancer Institute (NCI) R01CA188427 grant to V.G., the American Cancer Society Postdoctoral Fellowship (132722-PF-18-196-01-DMC) to HA, and the Horizon award under the Congressionally Directed Medical Research Program (CDMPRP), Department of Defense (DoD) (W81XWH-17-10509) to A.B.

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Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Hazem Abdelkarim
    • 1
  • Ben Hitchinson
    • 1
  • Avik Banerjee
    • 2
  • Vadim Gaponenko
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular Genetics, College of MedicineUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of ChemistryUniversity of Illinois at ChicagoChicagoUSA

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