PDBsum entry 1msm

Hydrolase/hydrolase inhibitor

PDB id: 1msm

Contents

Protein chains

99 a.a. *

Ligands

JE2

Waters ×145

* Residue conservation analysis

PDB id:

1msm

Name:

Hydrolase/hydrolase inhibitor

Title:

The HIV protease (mutant q7k l33i l63i) complexed with kni-764 (an inhibitor)

Structure:

Pol polyprotein. Chain: a, b. Fragment: HIV protease (residues 69-167). Engineered: yes

Source:

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

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.209 R-free: 0.236

Authors:

S.Vega,L.-W.Kang,A.Velazquez-Campoy,Y.Kiso,L.M.Amzel,E.Freire

Key ref:

S.Vega et al. (2004). A structural and thermodynamic escape mechanism from a drug resistant mutation of the HIV-1 protease. Proteins, 55, 594-602. PubMed id: 15103623 DOI: 10.1002/prot.20069

Date:

19-Sep-02 Release date: 04-Nov-03

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.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

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: 10.1002/prot.20069

Proteins 55:594-602 (2004)

PubMed id: 15103623

A structural and thermodynamic escape mechanism from a drug resistant mutation of the HIV-1 protease.

S.Vega, L.W.Kang, A.Velazquez-Campoy, Y.Kiso, L.M.Amzel, E.Freire.

ABSTRACT

The efficacy of HIV-1 protease inhibition therapies is often compromised by the appearance of mutations in the protease molecule that lower the binding affinity of inhibitors while maintaining viable catalytic activity and substrate affinity. The V82F/I84V double mutation is located within the binding site cavity and affects all protease inhibitors in clinical use. KNI-764, a second-generation inhibitor currently under development, maintains significant potency against this mutation by entropically compensating for enthalpic losses, thus minimizing the loss in binding affinity. KNI-577 differs from KNI-764 by a single functional group critical to the inhibitor response to the protease mutation. This single difference changes the response of the two inhibitors to the mutation by one order of magnitude. Accordingly, a structural understanding of the inhibitor response will provide important guidelines for the design of inhibitors that are less susceptible to mutations conveying drug resistance. The structures of the two compounds bound to the wild type and V82F/I84V HIV-1 protease have been determined by X-ray crystallography at 2.0 A resolution. The presence of two asymmetric functional groups, linked by rotatable bonds to the inhibitor scaffold, allows KNI-764 to adapt to the mutated binding site cavity more readily than KNI-577, with a single asymmetric group. Both inhibitors lose about 2.5 kcal/mol in binding enthalpy when facing the drug-resistant mutant protease; however KNI-764 gains binding entropy while KNI-577 loses binding entropy. The gain in binding entropy by KNI-764 accounts for its low susceptibility to the drug-resistant mutation. The heat capacity change associated with binding becomes more negative when KNI-764 binds to the mutant protease, consistent with increased desolvation. With KNI-577, the opposite effect is observed. Structurally, the crystallographic B factors increase for KNI-764 when it is bound to the drug-resistant mutant. The opposite is observed for KNI-577. Consistent with these observations, it appears that KNI-764 is able to gain binding entropy by a two-fold mechanism: it gains solvation entropy by burying itself deeper within the binding pocket and gains conformational entropy by losing interaction with the protease.

Selected figure(s)

Figure 2.
Figure 2. The chemical structure of KNI-577 (left) and KNI-764 (right). Both inhibitors share the same allophenyl-norstatine scaffold at the P1 position (red) and the same functional groups at the P2 (blue) and P1 positions (green). The only difference is at the P2 position (magenta).

Figure 4.
Figure 4. Superposition of the complexes of KNI-764 (left) and KNI-577 (right) bound to wild-type (cyan) and double mutant (purple) protease.

The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2004, 55, 594-602) copyright 2004.

Figures were selected by an automated process.