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

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

Author Laxmikanthan, G. Google Scholar
Blaber, S. I. Google Scholar
Bernett, M. J. Google Scholar
Scarisbrick, I. A. Google Scholar
Juliano, M. A. Google Scholar
Blaber, M. Google Scholar
Institution Florida State Univ
Mayo Clin & Mayo Grad Sch Med
Universidade Federal de São Paulo (UNIFESP)
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 Angstrom 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 (C) 2005 Wiley-Liss, Inc.
Keywords kallikrein
serine protease
substrate specificity
solvent structure
induced fit
Language English
Date 2005-03-01
Published in Proteins-structure Function and Bioinformatics. Hoboken: Wiley-liss, v. 58, n. 4, p. 802-814, 2005.
ISSN 0887-3585 (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 802-814
Origin http://dx.doi.org/10.1002/prot.20368
Access rights Closed access
Type Article
Web of Science ID WOS:000227106100004
URI http://repositorio.unifesp.br/handle/11600/28170

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