Molecular Playground/Prolyl Hydroxylase Domain (PHD) Enzyme: Difference between revisions
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=== Structure === | === Structure === | ||
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[[Image:PHD2.png|300 px|thumb|Fig. 1: Substrate bound (purple) and unbound (green) PHD2. Figure created with PyMol. PDB IDs 2G19, 3HQR.]] | |||
PHDs have two structural domains: the more variable N-terminal domain and the conserved catalytic C-terminal domain. The catalytic domain core of PHDs consists of eight β-strands in a "jelly-roll" or double stranded β helix <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Jelly_roll_fold/3'>(DSBH) fold motif</scene> supported by three conserved α-helices and other β-strands and loops that pack along the core. Possession of the DSBH motif is typical of 2-OG-dependent oxygenases. Contained in this core are the three Fe(II)-binding ligands formed by the conserved triad sequence, His-X-Asp/Glu-Xn-His.<ref name="review" /><ref>Schofield, C.J., Ratcliffe, P.J. "Signalling Bypoxia by HIF Hydroxylases." Biochemical and Biophysical Research Communications, August 24, 2005, 338, 617-626. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16139242 16139242]</ref><ref name="structure" /> | PHDs have two structural domains: the more variable N-terminal domain and the conserved catalytic C-terminal domain. The catalytic domain core of PHDs consists of eight β-strands in a "jelly-roll" or double stranded β helix <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Jelly_roll_fold/3'>(DSBH) fold motif</scene> supported by three conserved α-helices and other β-strands and loops that pack along the core. Possession of the DSBH motif is typical of 2-OG-dependent oxygenases. Contained in this core are the three Fe(II)-binding ligands formed by the conserved triad sequence, His-X-Asp/Glu-Xn-His.<ref name="review" /><ref>Schofield, C.J., Ratcliffe, P.J. "Signalling Bypoxia by HIF Hydroxylases." Biochemical and Biophysical Research Communications, August 24, 2005, 338, 617-626. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16139242 16139242]</ref><ref name="structure" /> | ||
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The <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Active_site/2'>active site</scene>, which is located on a deep cleft between the β-strands comprising the DBSH core, contains the essential Fe(II). It is normally coordinated by the conserved two-histidine-one-carboxylate <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Fe_binding_triad_sequence/2'>triad</scene>, 2-OG and a water molecule to form an octahedral geometry. Aside from the triad motif residues and those that bind 2-OG, the residues that are predominant inside the active site are nonpolar in nature. This is evidence of the enzyme's need to protect the protein core from oxidation by reactive species that are sometimes generated from iron-related reactions like the Fenton type reaction.<ref name="structure" /> | The <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Active_site/2'>active site</scene>, which is located on a deep cleft between the β-strands comprising the DBSH core, contains the essential Fe(II). It is normally coordinated by the conserved two-histidine-one-carboxylate <scene name='Sandbox_Prolyl_Hydroxylase_Domain_(PHD)_Enzyme/Fe_binding_triad_sequence/2'>triad</scene>, 2-OG and a water molecule to form an octahedral geometry. Aside from the triad motif residues and those that bind 2-OG, the residues that are predominant inside the active site are nonpolar in nature. This is evidence of the enzyme's need to protect the protein core from oxidation by reactive species that are sometimes generated from iron-related reactions like the Fenton type reaction.<ref name="structure" /> | ||
Upon binding of substrate β2β3 loop region of PHD2 goes to a large conformational change. β2β3 loop moves toward the active site and closes the active site entrance and it is believed to be essential for catalytic function of PHD2. β2β3 loop region is mostly conserved in PHDs with some differences. Mutational studies on β2β3 loop region has showed that this loop is significant for substrate recognition of PHDs<ref>PMID:18063574</ref>. | Upon binding of substrate β2β3 loop region of PHD2 goes to a large conformational change (Figure 1). β2β3 loop moves toward the active site and closes the active site entrance and it is believed to be essential for catalytic function of PHD2. β2β3 loop region is mostly conserved in PHDs with some differences. Mutational studies on β2β3 loop region has showed that this loop is significant for substrate recognition of PHDs<ref>PMID:18063574</ref>. | ||
=== Function === | === Function === | ||