A distinct binding mode of a hydroxyethylamine isostere inhibitor of HIV-1 protease.
Crystallization conditions for an HIV-1 protease-inhibitor complex were optimized to produce crystals suitable for X-ray diffraction experiments. The X-ray structure of the HIV-1 protease complex was solved and refined at 3.1 A resolution. In contrast to Saquinavir, the mimetic hydroxy group of the inhibitor Boc-Phe-Psi[(S)-CH(OH)CH(2)NH]-Phe-Glu-Phe-NH(2) is placed asymmetrically with respect to the non-crystallographic twofold axis of the protease dimer so that hydrogen bonds between the amino group of the inhibitor and the catalytic aspartates can be formed. The inhibitor binds in the centre of the active site by a compact network of hydrogen bonds to Gly27, Gly127, Asp25, Asp125 and via the buried water molecule W301 to Ile50 and Ile150.
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovského nám. 2, 162 06 Praha 6, Czech Republic. dohnalek@imc.cas.cz
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Dohnálek
J
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Hasek
J
J
Dusková
H
H
Petroková
M
M
Hradilek
M
M
Soucek
J
J
Konvalinka
J
J
Brynda
J
J
Sedlácek
M
M
Fábry
D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D003460:Crystallization; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation
D017320:HIV Protease Inhibitors; D001224:Aspartic Acid; D016333:HIV Protease