Sandbox Reserved 955: Difference between revisions
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'''Inhibitor structure''' | '''Inhibitor structure''' | ||
The sequence of the inhibitor JG-365 is Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe; the Ki is 0.24 nM. It's a protein with a length of 7 amino acid residues, composed of a C chain. 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 Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe; 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. | ||
'''HIV 1 protease structure''' | '''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 and A, B chains. 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 Asp-Thr-Gly 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. | 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 and A, B chains. 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 Asp-Thr-Gly 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> | ||
'''Binding site''' | '''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 bonding 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. | 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 bonding 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> | ||
Monomers appear to be directly related to inhibitor binding. One of these regions is the loop 49-52; 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 Ile-50 and Gly-51 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. | Monomers appear to be directly related to inhibitor binding. One of these regions is the loop 49-52; 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 Ile-50 and Gly-51 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. | ||