PDBsum entry 4bpi

Apoptosis

PDB id: 4bpi

Contents

Protein chains

141 a.a.

19 a.a.

Metals

_CD ×5

Waters ×17

PDB id:

4bpi

Name:

Apoptosis

Title:

Mcl-1 bound to alpha beta puma bh3 peptide 2

Structure:

Fusion protein consisting of induced myeloid leukemia cell differentiation protein mcl-1 homolog. Chain: a. Fragment: fusion protein of mouse mcl-1, residues 152-189 and human mcl-1, residues 209-327. Synonym: bcl-2-related protein eat/mcl1, bcl-2-like protein 3, bcl2- l-3, bcl-2-related protein eat/mcl1, mcl1/eat, mcl-1 bcl-2-like protein 3, bcl2-l-3, bcl-2-related protein eat/mcl1, mcl1/eat. Engineered: yes.

Source:

Mus musculus, homo sapiens. House mouse, human. Organism_taxid: 10090, 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606

Resolution:

1.98Å R-factor: 0.218 R-free: 0.243

Authors:

B.J.Smith,E.F.Lee,J.W.Checco,S.H.Gellman,W.D.Fairlie

Key ref:

B.J.Smith et al. (2013). Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. Chembiochem, 14, 1564-1572. PubMed id: 23929624 DOI: 10.1002/cbic.201300351

Date:

27-May-13 Release date: 09-Apr-14

Protein chain

P97287  (MCL1_MOUSE) -  Induced myeloid leukemia cell differentiation protein Mcl-1 homolog from Mus musculus

Seq: 331 a.a.

Struc: 141 a.a.*

Protein chain

Q07820  (MCL1_HUMAN) -  Induced myeloid leukemia cell differentiation protein Mcl-1 from Homo sapiens

Seq: 350 a.a.

Struc: 141 a.a.*

Protein chain

Q9BXH1  (BBC3_HUMAN) -  Bcl-2-binding component 3, isoforms 1/2 from Homo sapiens

Seq: 193 a.a.

Struc: 19 a.a.*

* PDB and UniProt seqs differ at 20 residue positions (black crosses)

DOI no: 10.1002/cbic.201300351

Chembiochem 14:1564-1572 (2013)

PubMed id: 23929624

Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.

B.J.Smith, E.F.Lee, J.W.Checco, M.Evangelista, S.H.Gellman, W.D.Fairlie.

ABSTRACT

We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived α/β-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three α residues of the original α/β backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new α/β-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners.