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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA, Jérémy Wagner

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 '''Inhibitor structure'''
-The sequence of the inhibitor JG-365 is<scene name='60/604474/Inhibitor/1'>Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe</scene>; the Ki is 0.24 nM. It's a protein with a length of 7 amino acid residues, composed of a C chain.<ref>http://www.rcsb.org/pdb/explore/explore.do?structureId=7hvp</ref> The inhibitor is positioned  in a single orientation in the protease active site with the flaps folded directly over it, protecting the inhibitor from bulk solvent.
+The sequence of the inhibitor JG-365 is<scene name='60/604474/Inhibitor/1'>Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe</scene>; the Ki is 0.24 nM. It's a protein with a length of 7 amino acid residues, composed of a C chain.<ref>http://www.rcsb.org/pdb/explore/explore.do?structureId=7hvp</ref>.The orientation of the inhibitor is a particular one in the protease active site, in fact its flaps are folded directly over it in order to protect it from bulk solvent.
 '''HIV 1 protease structure'''
+HIV-1 protease is a dimer  of identical polypeptide chains : it's composed of  two symmetrically related subunits, each consisting of 99 amino acid residues. Its structure is composed of A,B chains,<scene name='60/604474/Helix/1'>two helix</scene> (one in each subunit)and <scene name='60/604474/Sheets/2'>16 bêta sheets</scene>(8 in each subunits).
-HIV-1 protease is a dimer  of identical polypeptide chains : it's composed of  two symmetrically related subunits, each consisting of 99 amino acid residues. Its structure is composed of A,B chains,<scene name='60/604474/Helix/1'>two helix</scene> (one in each subunit)and <scene name='60/604474/Sheets/2'>16 bêta sheets</scene>(8 in each subunits).The subunits come together in such as way as to form a tunnel where they meet and in the inside of which  is located the active site of the protease. The active site consists of two <scene name='60/604474/Catalytic/5'>Asp-Thr-Gly</scene> conserved sequences, making it a member of the aspartyl protease family. The two Asp's are essential catalytic residues either interact with the incoming water or protonate the carbonyl to make the carbon more electrophilic for the incoming water. The two flexible flaps on the top of the tunnel  move to allow proteins to enter the tunnel. The flaps undergo a dramatic movement, shifting from an open to a closed conformation to bind the target in an appropriate conformation for cleavage. <ref>http://proteopedia.org/wiki/index.php/HIV-1_protease</ref>
+The active site of the protease is localised inside the tunnel forms by the two subunits of the protein which come together, and it consists of two <scene name='60/604474/Catalytic/5'>Asp-Thr-Gly</scene> conserved sequences, making it the member of the aspartyl protease family.On the top of this tunnel are txo flexible flaps which move to allow proteins to enter the tunnel and thus the catalytic site : they shift from an open to a closed conformation in order to bind the target in a correct conformation for cleavage.  The two Asp's are essential catalytic residues either interact with the incoming water or protonate the carbonyl to make the carbon more electrophilic for the incoming water. <ref>http://proteopedia.org/wiki/index.php/HIV-1_protease</ref>
 '''Binding site'''
-The hydroxyethylamine moiety, in place of the normal scissile bond of the substrate, is believed to mimic a tetrahedral reaction intermediate.The bound inhibitor diastereomer has the S configuration at the hydroxyethylamine chiral carbon, and the hydroxyl group is nestled between the side-chain carboxyl groups of the two active site aspartates within hydrogen bonding distance. The binding is asymmetric with Asp-25 slightly closer than Asp-125. In addition to the contact between the hydroxyl group on the tetrahedral carbon and the active site aspartates, polar contact between inhibitor and enzyme was made through only one substituent atom of the Asn-203 side chain.<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC55048/pdf/pnas01047-0128.pdf</ref>
+Instead of the classic scissile bond of the substrate,the hydroxyethylamine moiety is believed to mimic a tetrahedral reaction intermediate.The bound inhibitor diastereomer has the S configuration at the hydroxyethylamine chiral carbon, and the hydroxyl group is situated between the side-chain carboxyl groups of the two active site aspartates within hydrogen bonding distance.
-Monomers appear to be directly related to inhibitor binding. One of these regions is <scene name='60/604474/Loop/1'>the loop 49-52</scene> ; the difference between the alpha carbons upon superposition of Gly-49 and  Gly-149 is 1.6 A. These loop regions are the tips of the flaps that close over the inhibitor and provide some side-chain contacts to the hydrophobic binding pockets. The positions of these flaps are not equivalent because the peptide bond between residues <scene name='60/604474/Loop/3'>Ile 50 and Gly 51</scene> is turned 1800 compared with that between Ile-150 and Gly-151. This provides a means for a direct hydrogen bond between the tips of the flaps.
+The binding is not symmetric between the two Asp residues : Asp-25 is a little closer than Asp-125. Another aspect of this structure is that only one substituent atom of the Asn-203 side chain makes a polar contact, plus the contact between the hydroxyl group on the tetrahedral carbon and the active site apspartates.<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC55048/pdf/pnas01047-0128.pdf</ref>
+The monomers are directly related to inhibitor binding as this region, <scene name='60/604474/Loop/1'>the loop 49-52</scene>,shows it.The difference between the alpha carbons upon superposition of Gly-49 and  Gly-149 is 1.6 A. These loop regions correspond to the extremity of the flaps that close over the inhibitor and provide some side-chain contacts to the hydrophobic binding pockets. As <scene name='60/604474/Loop/3'>the picture</scene>shows, their position are not equivalent because of peptide bond between residues Ile-50 and Gly-51 is turned of 180° compared with Ile-150 and Gly-151 (the symmetrical residues in the other chain.In consequence a direct hydrogen bond between the extremity of the flaps is possible.