Structural Role of the 30's Loop in Determining the Ligand Specificity of the Human Immunodeficiency Virus Protease

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• 作者：Manal A. Swairjo ; Eric M. Towler ; Christine Debouck ; and Sherin S. Abdel-Meguid
• 刊名：Biochemistry
• 出版年：1998
• 出版时间：August 4, 1998
• 年：1998
• 卷：37
• 期：31
• 页码：10928 - 10936
• 全文大小：204K
• 年卷期：v.37,no.31(August 4, 1998)
• ISSN：1520-4995

文摘

The structural basis of ligand specificity in human immunodeficiency virus (HIV) proteasehas been investigated by determining the crystal structures of three chimeric HIV proteases complexedwith SB203386, a tripeptide analogue inhibitor. The chimeras are constructed by substituting amino acidresidues in the HIV type 1 (HIV-1) protease sequence with the corresponding residues from HIV type 2(HIV-2) in the region spanning residues 31-37 and in the active site cavity. SB203386 is a potent inhibitorof HIV-1 protease (K_i = 18 nM) but has a decreased affinity for HIV-2 protease (K_i = 1280 nM).Crystallographic analysis reveals that substitution of residues 31-37 (30's loop) with those of HIV-2protease renders the chimera similar to HIV-2 protease in both the inhibitor binding affinity and mode ofbinding (two inhibitor molecules per protease dimer). However, further substitution of active site residues47 and 82 has a compensatory effect which restores the HIV-1-like inhibitor binding mode (one inhibitormolecule in the center of the protease active site) and partially restores the affinity. Comparison of thethree chimeric protease structures with those of HIV-1 and SIV proteases complexed with the same inhibitorreveals structural changes in the flap regions and the 80's loops, as well as changes in the dimensions ofthe active site cavity. The study provides structural evidence of the role of the 30's loop in conferringinhibitor specificity in HIV proteases.