Use of 113Cd NMR to Probe the Native Metal Binding Sites in Metalloproteins: An Overview

  • Ian M. ArmitageEmail author
  • Torbjörn Drakenberg
  • Brian Reilly
Part of the Metal Ions in Life Sciences book series (MILS, volume 11)


Our laboratories have actively published in this area for several years and the objective of this chapter is to present as comprehensive an overview as possible. Following a brief review of the basic principles associated with 113Cd NMR methods, we will present the results from a thorough literature search for 113Cd chemical shifts from metalloproteins. The updated 113Cd chemical shift figure in this chapter will further illustrate the excellent correlation of the 113Cd chemical shift with the nature of the coordinating ligands (N, O, S) and coordination number/geometry, reaffirming how this method can be used not only to identify the nature of the protein ligands in uncharacterized cases but also the dynamics at the metal binding site. Specific examples will be drawn from studies on alkaline phosphatase, Ca2+ binding proteins, and metallothioneins.

In the case of Escherichia coli alkaline phosphatase, a dimeric zinc metalloenzyme where a total of six metal ions (three per monomer) are involved directly or indirectly in providing the enzyme with maximal catalytic activity and structural stability, 113Cd NMR, in conjunction with 13C and 31P NMR methods, were instrumental in separating out the function of each class of metal binding sites. Perhaps most importantly, these studies revealed the chemical basis for negative cooperativity that had been reported for this enzyme under metal deficient conditions. Also noteworthy was the fact that these NMR studies preceeded the availability of the X-ray crystal structure.

In the case of the calcium binding proteins, we will focus on two proteins: calbindin D9k and calmodulin. For calbindin D9k and its mutants, 113Cd NMR has been useful both to follow actual changes in the metal binding sites and the cooperativity in the metal binding. Ligand binding to calmodulin has been studied extensively with 113Cd NMR showing that the metal binding sites are not directly involved in the ligand binding. The 113Cd chemical shifts are, however, exquisitely sensitive to minute changes in the metal ion environment.

In the case of metallothionein, we will reflect upon how 113Cd substitution and the establishment of specific Cd to Cys residue connectivity by proton-detected heteronuclear 1H-113Cd multiple-quantum coherence methods (HMQC) was essential for the initial establishment of the 3D structure of metallothioneins, a protein family deficient in the regular secondary structural elements of α-helix and β-sheet and the first native protein identified with bound Cd. The 113Cd NMR studies also enabled the characterization of the affinity of the individual sites for 113Cd and, in competition experiments, for other divalent metal ions: Zn, Cu, and Hg.


alkaline phosphatase calbindin calcium-binding proteins calmodulin metallothionein 113Cd NMR methods 113Cd NMR chemical shifts from metalloproteins 



alkaline phosphatase


aztR gene product


cad operon transcription regulating protein




calcium-calmodulin-dependent protein kinase I


constitutive nitric oxide synthase


bacteriophage MU com gene product


chemical shift anisotropy




neuronal growth inhibitory factor


human carbonic anhydrase


heteronuclear multiple quantum correlation






nuclear magnetic resonance


nuclear Overhauser enhancement


HIV-1 nucleic acid binding protein


spin-lattice relaxation rate




residual dipolar coupling


small angle X-ray scattering


skeletal myosin light chain kinase




N-terminal half of calmodulin


C-terminal half of calmodulin



IMA would like to express his sincere appreciation to all the students and postdocs who have conducted the 113Cd NMR studies in his lab over the years and whose names can be found on the publications in the reference list. A special thanks is extended to his first postdoc, Dr. James D. Otvos, who embarked upon these studies at their outset in the mid 70s. A special thank you is also extended to Lewis Kay and Larry Werbelow for clarifying the correct treatment of relaxation rates and NOE for gyromagnetic ratios of opposite sign. We all thank Dr. Melanie Rogers for her assistance with both editing and formatting this chapter.

TD would like to dedicate this chapter to his long time colleague, Hans Lilja, who passed away last summer (2011). He was an electronics wizard and instumental to all our early NMR work. Hans you are dearly missed.


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Ian M. Armitage
    • 1
    Email author
  • Torbjörn Drakenberg
    • 2
  • Brian Reilly
    • 1
  1. 1.Department of Biochemistry, Molecular Biology, and BiophysicsUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Biophysical ChemistryLund UniversityLundSweden

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