PDBsum entry 1hpx

Hydrolase/hydrolase inhibitor

PDB id: 1hpx

Contents

Protein chains

99 a.a. *

Ligands

KNI

Waters ×6

* Residue conservation analysis

PDB id:

1hpx

Name:

Hydrolase/hydrolase inhibitor

Title:

HIV-1 protease complexed with the inhibitor kni-272

Structure:

HIV-1 protease. Chain: a, b. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: hivlai. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.170

Authors:

T.N.Bhat,J.W.Erickson

Key ref:

E.T.Baldwin et al. (1995). Structure of HIV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine. Structure, 3, 581-590. PubMed id: 8590019 DOI: 10.1016/S0969-2126(01)00192-7

Date:

18-May-95 Release date: 08-Mar-96

Protein chains

P03367  (POL_HV1BR) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI)

Seq: 1447 a.a.

Struc: 99 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.- - ?????
• Enzyme class 2: E.C.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 4: E.C.3.1.-.-
• Enzyme class 5: E.C.3.1.13.2 - exoribonuclease H.
• Reaction: Exonucleolytic cleavage to 5'-phosphomonoester oligonucleotides in both 5'- to 3'- and 3'- to 5'-directions.
• Enzyme class 6: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: E.C.3.4.23.16 - HIV-1 retropepsin.
• Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/S0969-2126(01)00192-7

Structure 3:581-590 (1995)

PubMed id: 8590019

Structure of HIV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine.

E.T.Baldwin, T.N.Bhat, S.Gulnik, B.Liu, I.A.Topol, Y.Kiso, T.Mimoto, H.Mitsuya, J.W.Erickson.

ABSTRACT

BACKGROUND: HIV-1 protease (HIV PR), an aspartic protease, cleaves Phe-Pro bonds in the Gag and Gag-Pol viral polyproteins. Substrate-based peptide mimics constitute a major class of inhibitors of HIV PR presently being developed for AIDS treatment. One such compound, KNI-272, which incorporates allophenylnorstatine (Apns)-thioproline (Thp) in place of Phe-Pro, has potent antiviral activity and is undergoing clinical trials. The structure of the enzyme-inhibitor complex should lead to an understanding of the structural basis for its tight binding properties and provide a framework for interpreting the emerging resistance to this drug. RESULTS: The three-dimensional crystal structure of KNI-272 bound to HIV PR has been determined to 2.0 A resolution and used to analyze structure-activity data and drug resistance for the Arg8-->Gln and ILe84-->Val mutations in HIV PR. The conformationally constrained Apns-Thp linkage is favorably recognized in its low energy trans conformation, which results in a symmetric mode of binding to the active-site aspartic acids and also explains the unusual preference of HIV PR for the S, or syn, hydroxyl group of the Apns residue. The inhibitor recognizes the enzyme via hydrogen bonds to three bridging water molecules, including one that is coordinated directly to the catalytic Asp125 residue. CONCLUSIONS: The structure of the HIV PR/KNI-272 complex illustrates the importance of limiting the conformational degrees of freedom and of using protein-bound water molecules for building potent inhibitors. The binding mode of HIV PR inhibitors can be predicted from the stereochemical relationship between adjacent hydroxyl-bearing and side chain bearing carbon atoms of the P1 substituent. Our structure also provides a framework for designing analogs targeted to drug-resistant mutant enzymes.

Selected figure(s)

Figure 5.
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. 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.

Figure 8.
Figure 8. Comparison of modeled epimer (R-hydroxyl) of KNI-272 (blue) with the anti conformers epi-Ro-31-8959 (yellow) and A-77003 (white). Nitrogen, oxygen and sulfur atoms are colored by type. (a) Comparison of all three. (b) Comparison of epi-KNI-272 and epi-Ro-31-8959 only. Figure 8. Comparison of modeled epimer (R-hydroxyl) of KNI-272 (blue) with the anti conformers epi-Ro-31-8959 (yellow) and A-77003 (white). Nitrogen, oxygen and sulfur atoms are colored by type. (a) Comparison of all three. (b) Comparison of epi-KNI-272 and epi-Ro-31-8959 only.

The above figures are reprinted by permission from Cell Press: Structure (1995, 3, 581-590) copyright 1995.

Figures were selected by an automated process.