PLoS ONE (Jan 2014)

High-quality NMR structure of human anti-apoptotic protein domain Mcl-1(171-327) for cancer drug design.

  • Gaohua Liu,
  • Leszek Poppe,
  • Ken Aoki,
  • Harvey Yamane,
  • Jeffrey Lewis,
  • Thomas Szyperski

DOI
https://doi.org/10.1371/journal.pone.0096521
Journal volume & issue
Vol. 9, no. 5
p. e96521

Abstract

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A high-quality NMR solution structure is presented for protein hMcl-1(171-327) which comprises residues 171-327 of the human anti-apoptotic protein Mcl-1 (hMcl-1). Since this construct contains the three Bcl-2 homology (BH) sequence motifs which participate in forming a binding site for inhibitors of hMcl-1, it is deemed to be crucial for structure-based design of novel anti-cancer drugs blocking the Mcl1 related anti-apoptotic pathway. While the coordinates of an NMR solution structure for a corresponding construct of the mouse homologue (mMcl-1) are publicly available, our structure is the first atomic resolution structure reported for the 'apo form' of the human protein. Comparison of the two structures reveals that hMcl-1(171-327) exhibits a somewhat wider ligand/inhibitor binding groove as well as a different charge distribution within the BH3 binding groove. These findings strongly suggest that the availability of the human structure is of critical importance to support future design of cancer drugs.