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

PLoS One. 2014 May 2;9(5):e96521. doi: 10.1371/journal.pone.0096521. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Binding Sites
  • Drug Design
  • Humans
  • Magnetic Resonance Spectroscopy / methods*
  • Mice
  • Models, Molecular
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein / chemistry*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / chemistry*
  • Protein Binding
  • Protein Structure, Tertiary*
  • Static Electricity

Substances

  • Antineoplastic Agents
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptide Fragments

Grant support

This study was funded by Amgen Inc. (www.amgen.com). LP, KA, HY and JL are employees of Amgen Inc. and Amgen Inc. played a role in study design, data collection and analysis, decision to publish and preparation of the manuscript.