X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease.
The crystal structure of ABT-378 (lopinavir), bound to the active site of HIV-1 protease is described. A comparison with crystal structures of ritonavir, A-78791, and BILA-2450 shows some analogous features with previous reported compounds. A cyclic urea unit in the P(2) position of ABT-378 is novel and makes two bidentate hydrogen bonds with Asp 29 of HIV-1 protease. In addition, a previously unreported shift in the Gly 48 carbonyl position is observed. A discussion of the structural features responsible for its high potency against wild-type HIV protease is given along with an analysis of the effect of active site mutations on potency in in vitro assays.
Stoll
Vincent
V
Department of Structural Biology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
Qin
Wenying
W
Stewart
Kent D
KD
Jakob
Clarissa
C
Park
Chang
C
Walter
K
K
Simmer
R L
RL
Helfrich
Rosalind
R
Bussiere
Dirk
D
Kao
J
J
Kempf
Dale
D
Sham
Hing L
HL
Norbeck
Daniel W
DW
D001665:Binding Sites / Q000235:genetics; D003460:Crystallization; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D061466:Lopinavir; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011744:Pyrimidinones / Q000737:chemistry*
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016333:HIV Protease