1. Volume 3, Issue 6, Pages 581-590 (June 1995)
Structure of HIV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine 
Eric T Baldwin, T.Narayana Bhat, Sergei Gulnik, Beishan Liu, Igor A Topol, Yoshiaki Kiso, Tsutomu Mimoto, Hiroaki Mitsuya, John W Erickson 
Structure 
Volume 3, Issue 6, Pages (June 1995)
DOI: /S (01)

2. Figure 1
Schematic drawing of KNI-272. Residue names are listed with their abbreviations in parentheses. By convention [33], substituents on N-  and C-terminal sides of the amide replacement are designed P and P′, respectively. The corresponding subsites in the enzyme are designated S and S′. Mean B-values were derived using all atoms in the individual groups as delineated by the dotted lines.
Structure 1995 3, DOI: ( /S (01) )

3. Figure 2
Stereo diagram showing the fit of KNI-272 to the 2.0 å OMIT map [34] of the KNI-272/HIV PR complex contoured at 2.0 σ. Difference map was calculated using X-PLOR 3.1 [31]. Atoms are colored by atom type; carbons are white.
Structure 1995 3, DOI: ( /S (01) )

4. Figure 3
Subsite interactions. (a–d) P1/S1 and P1′/S1′ interactions in the KNI-272/HIV PR complex. (a,b) van der Waals surfaces; (c,d) CPK space-filling model. (a,c) The phenyl group of the P1 Apns residue (shown in yellow) is held in a tight pocket formed by the side chains of Pro81, Val82, Ile84 and Gly149 of the neighboring flap, and stacks against the P3 iQoa ring (c). (b,d) The thioproline at P1′ interacts with residues Pro181 and Gly49 from the other chain of the dimeric enzyme. (e,f) CPK space-filling models of the P2/S2 and P2′/S2′ interactions in the KNI-272/HIV PR complex. Views are from the inhibitor looking into the subsite pockets. (g,h) van der Waals surface and space-filling model showing the interaction of the P3 iQoa group (yellow) with Arg8, Pro81 and the flap residues Gly149 and Phe153 within the S3 pocket. Carbon atoms of enzyme and inhibitor are colored pink and yellow, respectively; nitrogen, oxygen and sulfur atoms are colored by type.
Structure 1995 3, DOI: ( /S (01) )

5. Figure 4
Hydrogen bonds between the KNI-272 inhibitor and HIV-1 PR. (a) Schematic diagram; (b) structural model. Quantum chemistry calculations indicate that the hydroxyl group makes one hydrogen bond to Asp125 Oδ2, and that the carbonyl oxygen makes a hydrogen bond to Asp25 Oδ1 which is protonated (see text). The active-site pocket contains a water molecule, Wat607, which has not been reported in other HIV PR–peptidomimetic inhibitor complexes. Atoms are colored by type; carbons are pink.
Structure 1995 3, DOI: ( /S (01) )

6. Figure 4
Hydrogen bonds between the KNI-272 inhibitor and HIV-1 PR. (a) Schematic diagram; (b) structural model. Quantum chemistry calculations indicate that the hydroxyl group makes one hydrogen bond to Asp125 Oδ2, and that the carbonyl oxygen makes a hydrogen bond to Asp25 Oδ1 which is protonated (see text). The active-site pocket contains a water molecule, Wat607, which has not been reported in other HIV PR–peptidomimetic inhibitor complexes. Atoms are colored by type; carbons are pink.
Structure 1995 3, DOI: ( /S (01) )

7. Figure 5
View of the active site showing the symmetric mode of core binding for KNI-272. Bridging water molecules (red spheres) are observed in the S3 and S3′ subsites; these waters appear to stabilize the structure of the active-site pocket while also providing flexibility. Atoms are colored by type; carbons for the enzyme and inhibitor are pink and white, respectively.
Structure 1995 3, DOI: ( /S (01) )

8. Figure 6
Comparison of the structures of KNI-272 and the C2 symmetric inhibitor A (a) Bound inhibitor conformations after superposition of the enzyme portions only. The central carbon–carbon bond of the diol superposes with the carbon–carbon bond of the norstatine core. The P1 phenyl groups in the two structures overlap well, as do the Mta and tBu groups of KNI-272 with the P2 and P2′ valine groups of A The iQoa group of KNI-272 and the P3 pyridyl group of A occupy different locations. (b) Comparison of inhibitor–enzyme hydrogen-bond patterns. The amide nitrogen of the tBu group of KNI-272 hydrogen bonds to Wat608, which forms a bridging hydrogen bond to Asp29 amide nitrogen. Carbon atoms for KNI-272 and A are colored pink and gray, respectively; nitrogen, oxygen and sulfur atoms are colored by type.
Structure 1995 3, DOI: ( /S (01) )

9. Figure 6
Comparison of the structures of KNI-272 and the C2 symmetric inhibitor A (a) Bound inhibitor conformations after superposition of the enzyme portions only. The central carbon–carbon bond of the diol superposes with the carbon–carbon bond of the norstatine core. The P1 phenyl groups in the two structures overlap well, as do the Mta and tBu groups of KNI-272 with the P2 and P2′ valine groups of A The iQoa group of KNI-272 and the P3 pyridyl group of A occupy different locations. (b) Comparison of inhibitor–enzyme hydrogen-bond patterns. The amide nitrogen of the tBu group of KNI-272 hydrogen bonds to Wat608, which forms a bridging hydrogen bond to Asp29 amide nitrogen. Carbon atoms for KNI-272 and A are colored pink and gray, respectively; nitrogen, oxygen and sulfur atoms are colored by type.
Structure 1995 3, DOI: ( /S (01) )

10. Figure 7
Comparison of structures of KNI-272 and Ro (a) Bound inhibitor conformations after superposition of the enzyme portions only. (b) Hydrogen bonds and bridging waters. Both inhibitors utilize the syn hydroxyl configuration although the stereochemical naming rules result in opposite assignments: R-hydroxyl for Ro , and S-hydroxyl for KNI-272. Ro contains a quinoline group in P3, asparagine in P2, phenylalanine in P1 (connected via a hydroxyethylamine isostere to a decahydroquinoline moiety), and a tBu group at P2′. Carbon atoms for KNI-272 and Ro are pink and dark red, respectively; nitrogen, oxygen and sulfur atoms are colored by type. Coordinates for the Ro complex were kindly provided by K Appelt.
Structure 1995 3, DOI: ( /S (01) )

11. Figure 7
Comparison of structures of KNI-272 and Ro (a) Bound inhibitor conformations after superposition of the enzyme portions only. (b) Hydrogen bonds and bridging waters. Both inhibitors utilize the syn hydroxyl configuration although the stereochemical naming rules result in opposite assignments: R-hydroxyl for Ro , and S-hydroxyl for KNI-272. Ro contains a quinoline group in P3, asparagine in P2, phenylalanine in P1 (connected via a hydroxyethylamine isostere to a decahydroquinoline moiety), and a tBu group at P2′. Carbon atoms for KNI-272 and Ro are pink and dark red, respectively; nitrogen, oxygen and sulfur atoms are colored by type. Coordinates for the Ro complex were kindly provided by K Appelt.
Structure 1995 3, DOI: ( /S (01) )

12. Figure 8
Comparison of modeled epimer (R-hydroxyl) of KNI-272 (blue) with the anti conformers epi-Ro (yellow) and A (white). Nitrogen, oxygen and sulfur atoms are colored by type. (a) Comparison of all three. (b) Comparison of epi-KNI-272 and epi-Ro only.
Structure 1995 3, DOI: ( /S (01) )

13. Figure 9
Comparison of (a) P1′/S1′ and (b) P1/S1 interactions for the wild-type (upper) and Ile84→Val mutant (lower) complexes with KNI-272. CPK space-filling models show the loss of contact between the Cδ1 methyl of Ile84 or Ile184 (green sphere; upper) with the P1 and P1′ side chains of KNI-272. The model of the Ile84→Val mutant complex was built using the crystallographic coordinates of the wild-type complex. Carbon atoms of the enzyme and inhibitor are pink and yellow, respectively; nitrogen, oxygen, and sulfur atoms are colored by type, except Cδ1 of Ile84/184 (green).
Structure 1995 3, DOI: ( /S (01) )