Research Article

1.70 Å X-ray structure of human apo kallikrein 1: Structural changes upon peptide inhibitor/substrate binding†

  1. Gurunathan Laxmikanthan1,2,
  2. Sachiko I. Blaber1,
  3. Matthew J. Bernett1,2,
  4. Isobel A. Scarisbrick3,
  5. Maria Aparecida Juliano4,
  6. Michael Blaber1,2,*

Article first published online: 13 JAN 2005

DOI: 10.1002/prot.20368

Issue

Proteins: Structure, Function, and Bioinformatics

Proteins: Structure, Function, and Bioinformatics

Volume 58, Issue 4, pages 802–814, 1 March 2005

Additional Information

How to Cite

Laxmikanthan, G., Blaber, S. I., Bernett, M. J., Scarisbrick, I. A., Juliano, M. A. and Blaber, M. (2005), 1.70 Å X-ray structure of human apo kallikrein 1: Structural changes upon peptide inhibitor/substrate binding. Proteins: Structure, Function, and Bioinformatics, 58: 802–814. doi: 10.1002/prot.20368

Author Information

  1. 1

    Institute of Molecular Biophysics Florida State University, Tallahassee, Florida

  2. 2

    Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida

  3. 3

    Program for Molecular Neuroscience and Departments of Neurology, and Physical Medicine and Rehabilitation, Mayo Medical and Graduate Schools, Rochester, Minnesota

  4. 4

    Department of Biophysics, Universidade Federal de Sao Paulo, Escola Paulista de Medicina, Sao Paulo, Brazil

*406 Kasha Laboratory, Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306-3015

  1. †

    The atomic coordinates and structure factors (code 1SPJ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org).

Publication History

  1. Issue published online: 8 FEB 2005
  2. Article first published online: 13 JAN 2005
  3. Manuscript Accepted: 7 SEP 2004
  4. Manuscript Received: 3 AUG 2004

Funded by

  • National Multiple Sclerosis Society. Grant Number: RG3406-A-2
  • American Heart Association Predoctoral fellowship. Grant Number: 0315125B
  • Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP)

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Keywords:

  • kallikrein;
  • serine protease;
  • substrate specificity;
  • solvent structure;
  • induced fit

Abstract

Human kallikreins are serine proteases that comprise a recently identified large and closely related 15-member family. The kallikreins include both regulatory- and degradative-type proteases, impacting a variety of physiological processes including regulation of blood pressure, neuronal health, and the inflammatory response. While the function of the majority of the kallikreins remains to be elucidated, two members are useful biomarkers for prostate cancer and several others are potentially useful biomarkers for breast cancer, Alzheimer's, and Parkinson's disease. Human tissue kallikrein (human K1) is the best functionally characterized member of this family, and is known to play an important role in blood pressure regulation. As part of this function, human K1 exhibits unique dual-substrate specificity in hydrolyzing low molecular weight kininogen between both Arg-Ser and Met-Lys sequences. We report the X-ray crystal structure of mature, active recombinant human apo K1 at 1.70 Å resolution. The active site exhibits structural features intermediate between that of apo and pro forms of known kallikrein structures. The S2 to S2′ pockets demonstrate a variety of conformational changes in comparison to the porcine homolog of K1 in complex with peptide inhibitors, including the displacement of an extensive solvent network. These results indicate that the binding of a peptide substrate contributes to a structural rearrangement of the active-site Ser 195 resulting in a catalytically competent juxtaposition with the active-site His 57. The solvent networks within the S1 and S1′ pockets suggest how the Arg-Ser and Met-Lys dual substrate specificity of human K1 is accommodated. Proteins 2005. © 2005 Wiley-Liss, Inc.

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