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

Liu G, Poppe L, Aoki K, Yamane H, Lewis J, Szyperski T - PLoS ONE (2014)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, State University of New York at Buffalo, Buffalo, New York, United States of America.

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.

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Superposition of selected Mcl-1 structures.(A) Structures of hMcl-1(171–327) (green) and mMcl-1(152–308) (cyan, PDB accession code 1wsx) after superposition of the backbone N, Cα and C’ atoms of the α-helices for minimal rmsd. (B) Ribbon drawing (zoomed into (A)) showing the different binding groove widths of human (green) and mouse (cyan) protein. The distances between the Cα-atoms of residues His 224 in helix α2 (His 205 in mMcl-1) and His 252 (His 233 in mMcl-1) at the C-terminus of helix α3 are highlighted: ∼16 Å in hMcl-1(171–327) and ∼14 Å mMcl-1(152–308) (C) Superposition as in (A) of hMcl-1(171–327) (green) and mMcl-1(152–308) (cyan, 1wsx), and six selected Mcl-1 complex structures (see also Table 2): human Mcl-1 complexed with Bim BH3 (magenta, 2nla); chimeric rat-human rMcl-1(171–208)hMcl-1(209–327) complexed with mouse mNoxaB BH3 (yellow, 2rod); mouse mMcl-1(152–308) complexed with mouse NoxaA BH3 (pink, 2roc); mouse mMcl-1(152–308) complexed with mouse Puma BH3 (grey, 2jm6); mouse mMcl-1(152–308) complexed with mouse NoxaB BH3 (purple, 2rod); chimeric rat-human mMcl-1(171–208)hMcl-1(209–327) complexed with human Bim BH3 (orange, 2nl9); chimeric rat-human mMcl-1(171–208)hMcl-1(209–327) complexed with human Bim BH3(L62A, F68A) (light green, 3d7v).The figures were prepared with the programs MOLMOL [36] and PYMOL [37].
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pone-0096521-g003: Superposition of selected Mcl-1 structures.(A) Structures of hMcl-1(171–327) (green) and mMcl-1(152–308) (cyan, PDB accession code 1wsx) after superposition of the backbone N, Cα and C’ atoms of the α-helices for minimal rmsd. (B) Ribbon drawing (zoomed into (A)) showing the different binding groove widths of human (green) and mouse (cyan) protein. The distances between the Cα-atoms of residues His 224 in helix α2 (His 205 in mMcl-1) and His 252 (His 233 in mMcl-1) at the C-terminus of helix α3 are highlighted: ∼16 Å in hMcl-1(171–327) and ∼14 Å mMcl-1(152–308) (C) Superposition as in (A) of hMcl-1(171–327) (green) and mMcl-1(152–308) (cyan, 1wsx), and six selected Mcl-1 complex structures (see also Table 2): human Mcl-1 complexed with Bim BH3 (magenta, 2nla); chimeric rat-human rMcl-1(171–208)hMcl-1(209–327) complexed with mouse mNoxaB BH3 (yellow, 2rod); mouse mMcl-1(152–308) complexed with mouse NoxaA BH3 (pink, 2roc); mouse mMcl-1(152–308) complexed with mouse Puma BH3 (grey, 2jm6); mouse mMcl-1(152–308) complexed with mouse NoxaB BH3 (purple, 2rod); chimeric rat-human mMcl-1(171–208)hMcl-1(209–327) complexed with human Bim BH3 (orange, 2nl9); chimeric rat-human mMcl-1(171–208)hMcl-1(209–327) complexed with human Bim BH3(L62A, F68A) (light green, 3d7v).The figures were prepared with the programs MOLMOL [36] and PYMOL [37].

Mentions: Including our hMcl-1(171–327) structure, twenty atomic resolution structures containing different Mcl-1 constructs are currently deposited in the PDB. In addition to the two ‘apo’ proteins hMcl-1(171–327) and mouse mMcl-1(152–308) [10] [PDB accession code 1wsx, 89% sequence identity with the human protein], the structures for nineteen protein-ligand complexes were deposited (Table 2) [9],[11]–[18]. Clearly, the large number of available structures reflects the outstanding interest in Mcl-1 as a target for the development of new cancer drugs. Superposition of the α-helices reveals, as expected, close structural similarity for all Mcl-1 proteins structures (Figure 3): the root mean square deviation (rmsd) values range from 1.05 to 1.54 Å relative to hMcl1-1(171–327) (Table 2). However, comparison of the two apo protein structures of hMcl-1(171–327) and mMcl-1(152–308) with the complex structures shows that the binding pocket is widened upon complex formation (Table 2): the distances between the Cα-atoms of residues His 224 in helix α2 (His 205 in mMcl-1) and His 252 (His 233 in mMcl-1) at the C-terminus of helix α3 are, respectively, ∼16 Å and ∼14 Å in hMcl-1(171–327) and mMcl-1(152–308), and ∼18–21 Å in the complexes.


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

Liu G, Poppe L, Aoki K, Yamane H, Lewis J, Szyperski T - PLoS ONE (2014)

Superposition of selected Mcl-1 structures.(A) Structures of hMcl-1(171–327) (green) and mMcl-1(152–308) (cyan, PDB accession code 1wsx) after superposition of the backbone N, Cα and C’ atoms of the α-helices for minimal rmsd. (B) Ribbon drawing (zoomed into (A)) showing the different binding groove widths of human (green) and mouse (cyan) protein. The distances between the Cα-atoms of residues His 224 in helix α2 (His 205 in mMcl-1) and His 252 (His 233 in mMcl-1) at the C-terminus of helix α3 are highlighted: ∼16 Å in hMcl-1(171–327) and ∼14 Å mMcl-1(152–308) (C) Superposition as in (A) of hMcl-1(171–327) (green) and mMcl-1(152–308) (cyan, 1wsx), and six selected Mcl-1 complex structures (see also Table 2): human Mcl-1 complexed with Bim BH3 (magenta, 2nla); chimeric rat-human rMcl-1(171–208)hMcl-1(209–327) complexed with mouse mNoxaB BH3 (yellow, 2rod); mouse mMcl-1(152–308) complexed with mouse NoxaA BH3 (pink, 2roc); mouse mMcl-1(152–308) complexed with mouse Puma BH3 (grey, 2jm6); mouse mMcl-1(152–308) complexed with mouse NoxaB BH3 (purple, 2rod); chimeric rat-human mMcl-1(171–208)hMcl-1(209–327) complexed with human Bim BH3 (orange, 2nl9); chimeric rat-human mMcl-1(171–208)hMcl-1(209–327) complexed with human Bim BH3(L62A, F68A) (light green, 3d7v).The figures were prepared with the programs MOLMOL [36] and PYMOL [37].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008586&req=5

pone-0096521-g003: Superposition of selected Mcl-1 structures.(A) Structures of hMcl-1(171–327) (green) and mMcl-1(152–308) (cyan, PDB accession code 1wsx) after superposition of the backbone N, Cα and C’ atoms of the α-helices for minimal rmsd. (B) Ribbon drawing (zoomed into (A)) showing the different binding groove widths of human (green) and mouse (cyan) protein. The distances between the Cα-atoms of residues His 224 in helix α2 (His 205 in mMcl-1) and His 252 (His 233 in mMcl-1) at the C-terminus of helix α3 are highlighted: ∼16 Å in hMcl-1(171–327) and ∼14 Å mMcl-1(152–308) (C) Superposition as in (A) of hMcl-1(171–327) (green) and mMcl-1(152–308) (cyan, 1wsx), and six selected Mcl-1 complex structures (see also Table 2): human Mcl-1 complexed with Bim BH3 (magenta, 2nla); chimeric rat-human rMcl-1(171–208)hMcl-1(209–327) complexed with mouse mNoxaB BH3 (yellow, 2rod); mouse mMcl-1(152–308) complexed with mouse NoxaA BH3 (pink, 2roc); mouse mMcl-1(152–308) complexed with mouse Puma BH3 (grey, 2jm6); mouse mMcl-1(152–308) complexed with mouse NoxaB BH3 (purple, 2rod); chimeric rat-human mMcl-1(171–208)hMcl-1(209–327) complexed with human Bim BH3 (orange, 2nl9); chimeric rat-human mMcl-1(171–208)hMcl-1(209–327) complexed with human Bim BH3(L62A, F68A) (light green, 3d7v).The figures were prepared with the programs MOLMOL [36] and PYMOL [37].
Mentions: Including our hMcl-1(171–327) structure, twenty atomic resolution structures containing different Mcl-1 constructs are currently deposited in the PDB. In addition to the two ‘apo’ proteins hMcl-1(171–327) and mouse mMcl-1(152–308) [10] [PDB accession code 1wsx, 89% sequence identity with the human protein], the structures for nineteen protein-ligand complexes were deposited (Table 2) [9],[11]–[18]. Clearly, the large number of available structures reflects the outstanding interest in Mcl-1 as a target for the development of new cancer drugs. Superposition of the α-helices reveals, as expected, close structural similarity for all Mcl-1 proteins structures (Figure 3): the root mean square deviation (rmsd) values range from 1.05 to 1.54 Å relative to hMcl1-1(171–327) (Table 2). However, comparison of the two apo protein structures of hMcl-1(171–327) and mMcl-1(152–308) with the complex structures shows that the binding pocket is widened upon complex formation (Table 2): the distances between the Cα-atoms of residues His 224 in helix α2 (His 205 in mMcl-1) and His 252 (His 233 in mMcl-1) at the C-terminus of helix α3 are, respectively, ∼16 Å and ∼14 Å in hMcl-1(171–327) and mMcl-1(152–308), and ∼18–21 Å in the complexes.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, State University of New York at Buffalo, Buffalo, New York, United States of America.

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.

Show MeSH
Related in: MedlinePlus