Journal:Acta Cryst D:S2059798319000676
From Proteopedia
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<b>Molecular Tour</b><br> | <b>Molecular Tour</b><br> | ||
| - | L-pyroglutamate (pG) is formed by the cyclization of the side chain of glutamate or glutamine amino acid with alpha-amino group at the N-terminus of a polypeptide. This modified residue (pG) cannot be removed by any of the conventional peptidases. Special type of aminopeptidases called pyrrolidone-carboxylate peptidases (PCPs) (EC 3.4.19.-) can remove this unusual amino acid from the peptides or proteins. PCPs are of two types, a) PCPs I, which are cysteine peptidases of C15 family, b) PCPs II are metallopeptidases of M1 family. PCP I is highly conserved enzyme and its homologs have been found from bacteria to human. Many of the physiologically important peptide hormones (TRH, LHRH, GnRH) and antibodies have been shown to possess the pG residue at their N-termini. It seems to have implications in functional regulation of different peptides in both prokaryotes and eukaryotes. However, how these class of enzymes specifically catalyse the removal of pG residue remains mostly unknown. The crystal structures of PCP I from ''Deinococcus radiodurans'' (PCPdr) in its pG-free (PDB | + | L-pyroglutamate (pG) is formed by the cyclization of the side chain of glutamate or glutamine amino acid with alpha-amino group at the N-terminus of a polypeptide. This modified residue (pG) cannot be removed by any of the conventional peptidases. Special type of aminopeptidases called pyrrolidone-carboxylate peptidases (PCPs) (EC 3.4.19.-) can remove this unusual amino acid from the peptides or proteins. PCPs are of two types, a) PCPs I, which are cysteine peptidases of C15 family, b) PCPs II are metallopeptidases of M1 family. PCP I is highly conserved enzyme and its homologs have been found from bacteria to human. Many of the physiologically important peptide hormones (TRH, LHRH, GnRH) and antibodies have been shown to possess the pG residue at their N-termini. It seems to have implications in functional regulation of different peptides in both prokaryotes and eukaryotes. However, how these class of enzymes specifically catalyse the removal of pG residue remains mostly unknown. The crystal structures of PCP I from ''Deinococcus radiodurans'' (PCPdr) in its pG-free (PDB entry [[5z47]]) and pG-bound (PDB entry [[5z48]]) forms at high resolutions has helped to solve this puzzle. |
<scene name='80/806393/Cv/23'>Tetrameric structure of PCPdr is shown in cartoon representation</scene>. Each monomer is shown in different color. Bound substrate is shown in magenta spacefill representation. This tetrameric structure is similar to those observed in other PCP I proteins and buries equivalent surfaces of monomers for the formations of the tetramers. | <scene name='80/806393/Cv/23'>Tetrameric structure of PCPdr is shown in cartoon representation</scene>. Each monomer is shown in different color. Bound substrate is shown in magenta spacefill representation. This tetrameric structure is similar to those observed in other PCP I proteins and buries equivalent surfaces of monomers for the formations of the tetramers. | ||
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<scene name='80/806393/Cv/20'>Active-site of PCPdr with pG binding residues shown in ball-and-sticks and bound pG is shown in magenta ball-and-sticks</scene>. Water molecules are shown as red spheres. The presence of pG in the active site identifies the structural features that enable this enzyme to be a pG specific peptidase. pG is bound into a pocket formed by both hydrophobic and polar residues, Phe9, Phe12, Asn18, Val45, Gly70, Leu71, Tyr142, Val143, Cys144 and His169. The <scene name='80/806393/Cv/12'>residues of loop-A (residues 9-19)</scene> play a particularly important role in the pG binding. The <scene name='80/806393/Cv/13'>phenyl groups of Phe9 and Phe12 form stacking interactions with the aliphatic 2-pyrrolidone moiety of pG</scene> while the <scene name='80/806393/Cv/14'>ND2 of Asn18 forms a hydrogen bond with 2' oxygen of pyrrolidone moiety of pG</scene>. These residues are conserved in all the known PCPs I, including those from mammals. The residues from other loops also contribute significantly towards pG binding. The <scene name='80/806393/Cv/15'>main chain nitrogen and oxygen of Leu71 form two hydrogen bonds with OE and NH of pG</scene>, respectively. The adjacent residue, <scene name='80/806393/Cv/16'>Gly70</scene>, forms van der Waals contacts with OE of pG. Other van der Waals contacts for the pG binding are formed by the side chains of <scene name='80/806393/Cv/17'>Tyr142, Val143, Cys144 and Val45</scene>. The 5' carboxylate group of pG is held by several ionic interactions: <scene name='80/806393/Cv/18'>one of its carboxylate oxygen forms a hydrogen bond with NE2 of His169</scene> while the <scene name='80/806393/Cv/19'>other carboxylate oxygen interacts with the main chain N of catalytic Cys144 and a water molecule</scene>. This water molecule is further stabilized by its interactions with the residues Tyr142, Asn145, and Ala139. | <scene name='80/806393/Cv/20'>Active-site of PCPdr with pG binding residues shown in ball-and-sticks and bound pG is shown in magenta ball-and-sticks</scene>. Water molecules are shown as red spheres. The presence of pG in the active site identifies the structural features that enable this enzyme to be a pG specific peptidase. pG is bound into a pocket formed by both hydrophobic and polar residues, Phe9, Phe12, Asn18, Val45, Gly70, Leu71, Tyr142, Val143, Cys144 and His169. The <scene name='80/806393/Cv/12'>residues of loop-A (residues 9-19)</scene> play a particularly important role in the pG binding. The <scene name='80/806393/Cv/13'>phenyl groups of Phe9 and Phe12 form stacking interactions with the aliphatic 2-pyrrolidone moiety of pG</scene> while the <scene name='80/806393/Cv/14'>ND2 of Asn18 forms a hydrogen bond with 2' oxygen of pyrrolidone moiety of pG</scene>. These residues are conserved in all the known PCPs I, including those from mammals. The residues from other loops also contribute significantly towards pG binding. The <scene name='80/806393/Cv/15'>main chain nitrogen and oxygen of Leu71 form two hydrogen bonds with OE and NH of pG</scene>, respectively. The adjacent residue, <scene name='80/806393/Cv/16'>Gly70</scene>, forms van der Waals contacts with OE of pG. Other van der Waals contacts for the pG binding are formed by the side chains of <scene name='80/806393/Cv/17'>Tyr142, Val143, Cys144 and Val45</scene>. The 5' carboxylate group of pG is held by several ionic interactions: <scene name='80/806393/Cv/18'>one of its carboxylate oxygen forms a hydrogen bond with NE2 of His169</scene> while the <scene name='80/806393/Cv/19'>other carboxylate oxygen interacts with the main chain N of catalytic Cys144 and a water molecule</scene>. This water molecule is further stabilized by its interactions with the residues Tyr142, Asn145, and Ala139. | ||
| - | <scene name='80/806393/Cv1/11'>Structural conservation of loop-A in the crystal structures of PCPs from different prokaryotes</scene>. PCPdr (present study; gray); ''Thermus thermophlius'' (PDB entry [[2ebj]]; orange); ''Pyrococcus furiosus'' (PDB entry [[2df5]]; violet); ''Thermococcus litoralis'' (PDB entry [[1a2z]]; marine blue); ''Pyrococcus horikoshii'' (PDB entry [[1iu8]]; yellow); ''Bacillus amyloliquefaciens'' (PDB entry [[1aug]]; lime green); ''Bacillus anthrasis'' (PDB entry [[3lac]]; chocolate); ''Xenorhabdus bovienii'' (PDB entry [[4gxh]]; brown) and ''Staphylococcus aureus'' (PDB entry [[3giu]]; cyan). (Value in the bracket is reference of ''Bacillus amyloliquefaciens''). | + | <scene name='80/806393/Cv1/11'>Structural conservation of loop-A in the crystal structures of PCPs from different prokaryotes</scene>. PCPdr (present study; PDB entry [[5z47]]; gray); ''Thermus thermophlius'' (PDB entry [[2ebj]]; orange); ''Pyrococcus furiosus'' (PDB entry [[2df5]]; violet); ''Thermococcus litoralis'' (PDB entry [[1a2z]]; marine blue); ''Pyrococcus horikoshii'' (PDB entry [[1iu8]]; yellow); ''Bacillus amyloliquefaciens'' (PDB entry [[1aug]]; lime green); ''Bacillus anthrasis'' (PDB entry [[3lac]]; chocolate); ''Xenorhabdus bovienii'' (PDB entry [[4gxh]]; brown) and ''Staphylococcus aureus'' (PDB entry [[3giu]]; cyan). (Value in the bracket is reference of ''Bacillus amyloliquefaciens''). |
<b>References</b><br> | <b>References</b><br> | ||
Revision as of 08:38, 10 May 2022
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