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Molecular basis of Bcl-X(L)-p53 interaction: insights from molecular dynamics simulations.

Bharatham N, Chi SW, Yoon HS - PLoS ONE (2011)

Bottom Line: Bcl-X(L) and other Bcl-2 family proteins have 4 hydrophobic pockets (p1-p4), which are occupied by four systematically spaced hydrophobic residues (h1-h4) of the proapoptotic Bad and Bak BH3 peptides.We observed that three conserved hydrophobic residues (F19, W23 and L26) of p53 (SN15) peptide anchor into three hydrophobic pockets (p2-p4) of Bcl-X(L) in a similar manner as BH3 peptide.Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore.

ABSTRACT
Bcl-X(L), an antiapoptotic Bcl-2 family protein, plays a central role in the regulation of the apoptotic pathway. Heterodimerization of the antiapoptotic Bcl-2 family proteins with the proapoptotic family members such as Bad, Bak, Bim and Bid is a crucial step in the apoptotic regulation. In addition to these conventional binding partners, recent evidences reveal that the Bcl-2 family proteins also interact with noncanonical binding partners such as p53. Our previous NMR studies showed that Bcl-X(L): BH3 peptide and Bcl-X(L): SN15 peptide (a peptide derived from residues S15-N29 of p53) complex structures share similar modes of bindings. To further elucidate the molecular basis of the interactions, here we have employed molecular dynamics simulations coupled with MM/PBSA approach. Bcl-X(L) and other Bcl-2 family proteins have 4 hydrophobic pockets (p1-p4), which are occupied by four systematically spaced hydrophobic residues (h1-h4) of the proapoptotic Bad and Bak BH3 peptides. We observed that three conserved hydrophobic residues (F19, W23 and L26) of p53 (SN15) peptide anchor into three hydrophobic pockets (p2-p4) of Bcl-X(L) in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.

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Hydrogen bonding pattern of p53 tryptophan residue.W23 residue of p53 or SN15 forms stable hydrogen bonding interaction with main chain carbonyl of E96 of Bcl-XL are shown (A). Hydrogen bond interaction between W23 of p53 and main chain carbonyl of L54 residue of MDM2 are shown (B). Hydrogen bond represented with black dotted line.
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pone-0026014-g006: Hydrogen bonding pattern of p53 tryptophan residue.W23 residue of p53 or SN15 forms stable hydrogen bonding interaction with main chain carbonyl of E96 of Bcl-XL are shown (A). Hydrogen bond interaction between W23 of p53 and main chain carbonyl of L54 residue of MDM2 are shown (B). Hydrogen bond represented with black dotted line.

Mentions: Another important similarity in binding pattern of p53 with Bcl-XL and MDM2 (Figure 6) is the stable hydrogen bond interaction between epsilon nitrogen atom of tryptophan (W23) side chain and main chain carbonyl of E96 (Bcl-XL), L54 (MDM2). Our simulations results in the present study postulated that P27 of SN15 covers the first hydrophobic pocket (p1) and forms van der Waals interactions with L112, V126 and F146. Recent crystal structures of MDM2 and MDMX with PMI (p53 based mutant peptide inhibitors) revealed that both the protein surfaces have an extra 4th hydrophobic pocket. The proline residue which is present at C-terminal end of PMI (TSFAEYWNLLSP) occupies this extra binding pocket (Figure S6) of MDMX formed by V49, M53, Y99 and L102. In MDM2 the equivalent residues are M50, L54, Y100 and I103. Surprisingly this pocket is unable to accommodate the proline residue of PMI due to the Y100 conformation. The point mutation studies clearly indicated that the proline change affects negatively on binding with MDMX protein. Despite these differences it's clear that these two proteins have 4th hydrophobic pocket similar as Bcl-2 proteins.


Molecular basis of Bcl-X(L)-p53 interaction: insights from molecular dynamics simulations.

Bharatham N, Chi SW, Yoon HS - PLoS ONE (2011)

Hydrogen bonding pattern of p53 tryptophan residue.W23 residue of p53 or SN15 forms stable hydrogen bonding interaction with main chain carbonyl of E96 of Bcl-XL are shown (A). Hydrogen bond interaction between W23 of p53 and main chain carbonyl of L54 residue of MDM2 are shown (B). Hydrogen bond represented with black dotted line.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198449&req=5

pone-0026014-g006: Hydrogen bonding pattern of p53 tryptophan residue.W23 residue of p53 or SN15 forms stable hydrogen bonding interaction with main chain carbonyl of E96 of Bcl-XL are shown (A). Hydrogen bond interaction between W23 of p53 and main chain carbonyl of L54 residue of MDM2 are shown (B). Hydrogen bond represented with black dotted line.
Mentions: Another important similarity in binding pattern of p53 with Bcl-XL and MDM2 (Figure 6) is the stable hydrogen bond interaction between epsilon nitrogen atom of tryptophan (W23) side chain and main chain carbonyl of E96 (Bcl-XL), L54 (MDM2). Our simulations results in the present study postulated that P27 of SN15 covers the first hydrophobic pocket (p1) and forms van der Waals interactions with L112, V126 and F146. Recent crystal structures of MDM2 and MDMX with PMI (p53 based mutant peptide inhibitors) revealed that both the protein surfaces have an extra 4th hydrophobic pocket. The proline residue which is present at C-terminal end of PMI (TSFAEYWNLLSP) occupies this extra binding pocket (Figure S6) of MDMX formed by V49, M53, Y99 and L102. In MDM2 the equivalent residues are M50, L54, Y100 and I103. Surprisingly this pocket is unable to accommodate the proline residue of PMI due to the Y100 conformation. The point mutation studies clearly indicated that the proline change affects negatively on binding with MDMX protein. Despite these differences it's clear that these two proteins have 4th hydrophobic pocket similar as Bcl-2 proteins.

Bottom Line: Bcl-X(L) and other Bcl-2 family proteins have 4 hydrophobic pockets (p1-p4), which are occupied by four systematically spaced hydrophobic residues (h1-h4) of the proapoptotic Bad and Bak BH3 peptides.We observed that three conserved hydrophobic residues (F19, W23 and L26) of p53 (SN15) peptide anchor into three hydrophobic pockets (p2-p4) of Bcl-X(L) in a similar manner as BH3 peptide.Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore.

ABSTRACT
Bcl-X(L), an antiapoptotic Bcl-2 family protein, plays a central role in the regulation of the apoptotic pathway. Heterodimerization of the antiapoptotic Bcl-2 family proteins with the proapoptotic family members such as Bad, Bak, Bim and Bid is a crucial step in the apoptotic regulation. In addition to these conventional binding partners, recent evidences reveal that the Bcl-2 family proteins also interact with noncanonical binding partners such as p53. Our previous NMR studies showed that Bcl-X(L): BH3 peptide and Bcl-X(L): SN15 peptide (a peptide derived from residues S15-N29 of p53) complex structures share similar modes of bindings. To further elucidate the molecular basis of the interactions, here we have employed molecular dynamics simulations coupled with MM/PBSA approach. Bcl-X(L) and other Bcl-2 family proteins have 4 hydrophobic pockets (p1-p4), which are occupied by four systematically spaced hydrophobic residues (h1-h4) of the proapoptotic Bad and Bak BH3 peptides. We observed that three conserved hydrophobic residues (F19, W23 and L26) of p53 (SN15) peptide anchor into three hydrophobic pockets (p2-p4) of Bcl-X(L) in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.

Show MeSH