PDBsum entry 1ztz

Hydrolase

PDB id: 1ztz

Contents

Protein chains

99 a.a. *

Ligands

ALA-GLY-ALA-ALA

CB5 ×2

Waters ×202

* Residue conservation analysis

PDB id:

1ztz

Name:

Hydrolase

Title:

Crystal structure of HIV protease- metallacarborane complex

Structure:

Protease retropepsin. Chain: a, b. Synonym: HIV-1 protease. Engineered: yes. Mutation: yes. Autoproteolytic tetrapeptide. Chain: p. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: gag-pol. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes

Biol. unit:

Hexamer (from PQS)

Resolution:

2.15Å R-factor: 0.179 R-free: 0.233

Authors:

P.Cigler,M.Kozisek,P.Rezacova,J.Brynda,Z.Otwinowski,J.Sedlacek, J.Bodem,H.-G.Kraeusslich,V.Kral,J.Konvalinka

Key ref:

P.Cígler et al. (2005). From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease. Proc Natl Acad Sci U S A, 102, 15394-15399. PubMed id: 16227435 DOI: 10.1073/pnas.0507577102

Date:

28-May-05 Release date: 01-Nov-05

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.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 2: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: 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 4: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 5: 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: 10.1073/pnas.0507577102

Proc Natl Acad Sci U S A 102:15394-15399 (2005)

PubMed id: 16227435

From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease.

P.Cígler, M.Kozísek, P.Rezácová, J.Brynda, Z.Otwinowski, J.Pokorná, J.Plesek, B.Grüner, L.Dolecková-Maresová, M.Mása, J.Sedlácek, J.Bodem, H.G.Kräusslich, V.Král, J.Konvalinka.

ABSTRACT

HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition.

Selected figure(s)

Figure 1.
Fig. 1. Ring opening reaction of 8-dioxane-3-cobalt bis(1,2-dicarbollide) 7 by different nucleofiles Nu0 (e.g., NH[3]) and Nu- (e.g., RO-) yielding zwitterionic and anionic compounds, respectively.

Figure 3.
Fig. 3. Interactions of compound 1 with the amino acid residues in the corresponding PR-binding pocket. (A) Binding of compound 1 molecule Cb1 by PR monomer A (red tube). (B) Binding of compound 1 molecule Cb2 by PR monomer B (blue tube). Compound 1 is represented by a stick model in gray, with cobalt shown as a magenta sphere. PR residues in contact with compound 1 are represented by stick models, and their solvent-accessible surfaces are colored by atom charge (blue, positive; red, negative). (C) Superposition of the two compound 1-binding modes. The color scheme and representation for PR is the same as in A and B, and atoms in compound 1 are colored with the color of the interacting PR chain.

Figures were selected by an automated process.