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Structure and function of SET and MYND domain-containing proteins.

Spellmon N, Holcomb J, Trescott L, Sirinupong N, Yang Z - Int J Mol Sci (2015)

Bottom Line: SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell cycle control.During early development, SMYD proteins are believed to act as an epigenetic regulator for myogenesis and cardiomyocyte differentiation as they are abundantly expressed in cardiac and skeletal muscle.This review will examine the biological relevance and gather all of the current structural data of SMYD proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 East Canfield Street, Detroit, MI 48201, USA. nicholas.spellmon@wayne.edu.

ABSTRACT
SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell cycle control. During early development, SMYD proteins are believed to act as an epigenetic regulator for myogenesis and cardiomyocyte differentiation as they are abundantly expressed in cardiac and skeletal muscle. SMYD proteins are also of therapeutic interest due to the growing list of carcinomas and cardiovascular diseases linked to SMYD overexpression or dysfunction making them a putative target for drug intervention. This review will examine the biological relevance and gather all of the current structural data of SMYD proteins.

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Related in: MedlinePlus

AZ505-bound SMYD2 structure. (A) Interactions between AZ505 and SMYD2. AZ505 is depicted by balls-and-sticks with the carbon atoms colored in white. SMYD2 residues are depicted by sticks colored according to domains; (B) Comparison of the binding sites of ERα, p53, and AZ505. The ERα and p53 peptides are depicted by sticks and colored in yellow and blue. AZ505 is represented in the same way as in (A); and (C) Surface representation of SMYD2–ERα structure illustrates potential drug targeting sites: ERα (yellow), p53 (blue), PEG (purple), Hsp90 (light blue), the ribosomal peptide (orange), and proline-rich peptide (hot pink). SAH and AZ505 are depicted by sticks.
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ijms-16-01406-f008: AZ505-bound SMYD2 structure. (A) Interactions between AZ505 and SMYD2. AZ505 is depicted by balls-and-sticks with the carbon atoms colored in white. SMYD2 residues are depicted by sticks colored according to domains; (B) Comparison of the binding sites of ERα, p53, and AZ505. The ERα and p53 peptides are depicted by sticks and colored in yellow and blue. AZ505 is represented in the same way as in (A); and (C) Surface representation of SMYD2–ERα structure illustrates potential drug targeting sites: ERα (yellow), p53 (blue), PEG (purple), Hsp90 (light blue), the ribosomal peptide (orange), and proline-rich peptide (hot pink). SAH and AZ505 are depicted by sticks.

Mentions: Efforts to create SMYD inhibitors are currently underway. AZ505 is a potent SMYD2 competitive inhibitor recently identified from a high throughput chemical screening [29]. In the crystal structure, AZ505 bound to the lysine access channel, and ITC analysis indicated inhibitor binding is primarily driven by hydrophobic interactions providing a low KD ~0.5 μM (Figure 8A) [29]. The three moieties of AZ505 have similar interactions found in the p53 and ERα peptides. The benzooxazinone group is packaged into the lysine channel where several hydrophobic and electrostatic interactions are made (Figure 8A). The cyclohexyl and dichlorophenethyl groups adopt the same −1 and −2 position, but they appear more compact to the surface than the p53 and ERα peptides (Figure 8B). In addition, the Gly183 carbonyl oxygen forms a similar hydrogen bond to the amide linker between the benzooxazinone and cyclohexyl groups. Therefore, the potency of AZ505 appears to be due to a complete blockage of the core region of the SMYD2 active site and preventing it from binding to the target lysine.


Structure and function of SET and MYND domain-containing proteins.

Spellmon N, Holcomb J, Trescott L, Sirinupong N, Yang Z - Int J Mol Sci (2015)

AZ505-bound SMYD2 structure. (A) Interactions between AZ505 and SMYD2. AZ505 is depicted by balls-and-sticks with the carbon atoms colored in white. SMYD2 residues are depicted by sticks colored according to domains; (B) Comparison of the binding sites of ERα, p53, and AZ505. The ERα and p53 peptides are depicted by sticks and colored in yellow and blue. AZ505 is represented in the same way as in (A); and (C) Surface representation of SMYD2–ERα structure illustrates potential drug targeting sites: ERα (yellow), p53 (blue), PEG (purple), Hsp90 (light blue), the ribosomal peptide (orange), and proline-rich peptide (hot pink). SAH and AZ505 are depicted by sticks.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307310&req=5

ijms-16-01406-f008: AZ505-bound SMYD2 structure. (A) Interactions between AZ505 and SMYD2. AZ505 is depicted by balls-and-sticks with the carbon atoms colored in white. SMYD2 residues are depicted by sticks colored according to domains; (B) Comparison of the binding sites of ERα, p53, and AZ505. The ERα and p53 peptides are depicted by sticks and colored in yellow and blue. AZ505 is represented in the same way as in (A); and (C) Surface representation of SMYD2–ERα structure illustrates potential drug targeting sites: ERα (yellow), p53 (blue), PEG (purple), Hsp90 (light blue), the ribosomal peptide (orange), and proline-rich peptide (hot pink). SAH and AZ505 are depicted by sticks.
Mentions: Efforts to create SMYD inhibitors are currently underway. AZ505 is a potent SMYD2 competitive inhibitor recently identified from a high throughput chemical screening [29]. In the crystal structure, AZ505 bound to the lysine access channel, and ITC analysis indicated inhibitor binding is primarily driven by hydrophobic interactions providing a low KD ~0.5 μM (Figure 8A) [29]. The three moieties of AZ505 have similar interactions found in the p53 and ERα peptides. The benzooxazinone group is packaged into the lysine channel where several hydrophobic and electrostatic interactions are made (Figure 8A). The cyclohexyl and dichlorophenethyl groups adopt the same −1 and −2 position, but they appear more compact to the surface than the p53 and ERα peptides (Figure 8B). In addition, the Gly183 carbonyl oxygen forms a similar hydrogen bond to the amide linker between the benzooxazinone and cyclohexyl groups. Therefore, the potency of AZ505 appears to be due to a complete blockage of the core region of the SMYD2 active site and preventing it from binding to the target lysine.

Bottom Line: SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell cycle control.During early development, SMYD proteins are believed to act as an epigenetic regulator for myogenesis and cardiomyocyte differentiation as they are abundantly expressed in cardiac and skeletal muscle.This review will examine the biological relevance and gather all of the current structural data of SMYD proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 East Canfield Street, Detroit, MI 48201, USA. nicholas.spellmon@wayne.edu.

ABSTRACT
SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell cycle control. During early development, SMYD proteins are believed to act as an epigenetic regulator for myogenesis and cardiomyocyte differentiation as they are abundantly expressed in cardiac and skeletal muscle. SMYD proteins are also of therapeutic interest due to the growing list of carcinomas and cardiovascular diseases linked to SMYD overexpression or dysfunction making them a putative target for drug intervention. This review will examine the biological relevance and gather all of the current structural data of SMYD proteins.

Show MeSH
Related in: MedlinePlus