A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1

PLoS One. 2015 Apr 24;10(4):e0125010. doi: 10.1371/journal.pone.0125010. eCollection 2015.

Abstract

Crystallization of a maltose-binding protein MCL1 fusion has yielded a robust crystallography platform that generated the first apo MCL1 crystal structure, as well as five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In the ligand-independent crystal form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1 construct dramatically improves the structural understanding of well-validated MCL1 ligands, and will likely catalyze the structure-based optimization of high affinity MCL1 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoproteins / chemistry
  • Apoproteins / genetics
  • Crystallization
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Ligands
  • Maltose-Binding Proteins / chemistry*
  • Maltose-Binding Proteins / genetics
  • Models, Molecular
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein / chemistry*
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Protein Binding
  • Protein Conformation
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics

Substances

  • Apoproteins
  • Ligands
  • MCL1 protein, human
  • Maltose-Binding Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptide Fragments
  • Recombinant Fusion Proteins

Grant support

This study was funded by the Broad Institute with generous support from the Carlos Slim Health Institute and the Robertson Foundation. AL, BF, D. Daniels, GW, AB, TRG, BKH, and MSW are employees of the Broad Institute and received funding for this study in the form of a salary. MCC, D. Dranow, JWF, JA, KAA, and EW are employees of Beryllium and received funding for this study in the form of a salary. DF, ZN, and GX are employees of Acme Bioscience and received funding for this study in the form of a salary. JVD is the sole proprietor of Van Drie Research and received funding for this study in the form of a salary. The Broad Institute, Beryllium, Acme, and Van Drie Research played a role in study design, data collection and analysis, decision to publish and preparation of the manuscript.