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Science 2 October 1992:
Vol. 258. no. 5079, pp. 130 - 135
DOI: 10.1126/science.1439761
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Articles

Science, Vol 258, Issue 5079, 130-135
Copyright © 1992 by American Association for the Advancement of Science

articles

Structural basis of the intrasteric regulation of myosin light chain kinases

DR Knighton, RB Pearson, JM Sowadski, AR Means, LF Ten Eyck, SS Taylor, and BE Kemp

Department of Chemistry, University of California San Diego, La Jolla 92093-0654.

The smooth muscle myosin light chain kinase (smMLCK) catalytic core was modeled by using the crystallographic coordinates of the cyclic AMP-dependent protein kinase catalytic subunit (cAPK) and a bound pseudosubstrate inhibitor peptide, PKI(5-24). Despite only 30% identity in amino acid sequence, the MLCK sequence can be readily accommodated in this structure. With the exception of the short B-helix, all major elements of secondary structure in the core are very likely conserved. The active site of the modeled MLCK complements the known requirements for peptide substrate recognition. MLCK contains a pseudosubstrate sequence that overlaps the calmodulin binding domain and has been proposed to act as an intrasteric inhibitor and occupy the substrate binding site in the absence of Ca(2+)-calmodulin. The pseudosubstrate sequence can be modeled easily into the entire backbone of PKI(5-24). The results demonstrate that the intrasteric model for regulation of MLCK by intramolecular competitive inhibition is structurally plausible.


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