PDBsum entry 3kdb

Hydrolase/hydrolase inhibitor

PDB id: 3kdb

Contents

Protein chains

99 a.a. *

Ligands

GOL

006

Waters ×233

* Residue conservation analysis

PDB id:

3kdb

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of HIV-1 protease (q7k, l33i, l63i) in complex with kni-10006

Structure:

Protease. Chain: a, b. Fragment: unp residues 501-599. Synonym: retropepsin, pr. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus type 1. HIV-1. Organism_taxid: 11686. Strain: subtype b. Gene: gag-pol. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.66Å R-factor: 0.214 R-free: 0.255

Authors:

E.E.Chufan,V.Lafont,E.Freire,L.M.Amzel

Key ref:

Y.Kawasaki et al. (2010). How much binding affinity can be gained by filling a cavity? Chem Biol Drug Des, 75, 143-151. PubMed id: 20028396

Date:

22-Oct-09 Release date: 02-Mar-10

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

Chem Biol Drug Des 75:143-151 (2010)

PubMed id: 20028396

How much binding affinity can be gained by filling a cavity?

Y.Kawasaki, E.E.Chufan, V.Lafont, K.Hidaka, Y.Kiso, L.Mario Amzel, E.Freire.

ABSTRACT

Binding affinity optimization is critical during drug development. Here, we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (-H, -F, -Cl, and CH(3)) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this article, the enthalpy gain amounts to -1.5 kcal/mol while the entropic losses amount to +0.9 kcal/mol resulting in a net 3.5-fold affinity gain. The second phase is characterized by simultaneous enthalpic and entropic gains. This phase improves the binding affinity 25-fold. The third phase represents the collapse of the trend and is triggered by the introduction of chemical functionalities larger than the binding cavity itself [CH(CH(3))(2)]. It is characterized by large enthalpy and affinity losses. The thermodynamic signatures associated with each phase provide guidelines for lead optimization.