Toward Understanding Mcl-1 Promiscuous and Specific Binding Mode

Abstract

Mcl-1, which is an anti-apoptotic member of the Bcl-2 protein family, is overexpressed in various cancers and promotes the aberrant survival of tumor cells. To inhibit Mcl-1, and initiate apoptosis, an interaction between BH3-only proteins and Mcl-1 anti-apoptotic protein is necessary. These protein-protein interactions exhibit some selectivity: Mcl-1 binds specifically to Noxa, whereas Bim and Puma bind strongly to all anti-apoptotic proteins. Even if the three-dimensional (3D) structures of several Mcl-1/BH3-only complexes have been solved, the BH3-only binding specificity to Mcl-1 is still not completely understood. In this study, molecular dynamics simulations were used to elucidate the molecular basis of the interactions with Mcl-1. Our results corroborate the importance of four conserved hydrophobic residues and a conserved aspartic acid on BH3-only as a common binding pattern. Furthermore, our results highlight the contribution of the fifth hydrophobic residue in the C-terminal part and a negatively charged patch in the N-terminal of BH3-only peptides as important for their fixation to Mcl-1. We hypothesize that this negatively charged patch will be an Mcl-1 specific binding pattern.

Hot-Spots of Mcl-1 Protein

“…The Asn260 is close to Arg263 and the P4 pocket, and Phe319 is located after the P4 pocket. These experimental results were also confirmed by molecular modeling simulations. − …”

Understanding MCL1: from cellular function and regulation to pharmacological inhibition

“…3A ). An aspartic acid residue from the BH3 domain forms a salt bridge with arginine 263 of the MCL1‐binding groove [ 15 , 16 , 17 , 18 ].…”

Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1

“…The experimental details show that the three-dimensional structure of Mcl1 is tightly packed with a series of amphipathic α-helical bundles [10][11][12]. These α-helical bundles are arranged in such a manner that they form a distinct binding groove on the surface of Mcl1 [12][13][14][15][16]. This binding groove covers a large surface area, and is occupied by an ensemble of hydrophobic residues providing an excellent spot to accommodate its partners from other family members (PAP or BH3-only peptides) or the non-peptide substances [10].…”

“…These hydrophobic residues inside the pocket are (i) highly conserved, (ii) remain crucial for binding partner selectivity, and (iii) are also the main reason for showing a wide range of binding affinity values when interacting with its binding partner for apoptotic regulation. For example, cytochrome c release is highly affected due to the sequestration of Bak by Mcl1 activity; the Bim protein can bind with all the members of AAPs, while Noxa proteins show high selectivity with Mcl1 [15,17]. These notable characters of Mcl1 make it a highly challenging therapeutic target, and also remind us of the need for novel cancer drug development [18].…”