PDBsum entry 2p3b

Hydrolase/hydrolase inhibitor

PDB id: 2p3b

Contents

Protein chains

99 a.a. *

99 a.a. *

Ligands

3TL

Waters ×98

* Residue conservation analysis

PDB id:

2p3b

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of the subtype b wild type HIV protease complexed with tl-3 inhibitor

Structure:

Protease. Chain: a. Engineered: yes. Other_details: cys at position 67. Protease. Chain: b. Engineered: yes. Other_details: cme at position 67

Source:

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

Resolution:

2.10Å R-factor: 0.165 R-free: 0.219

Authors:

M.Sanches,S.Krauchenco,N.H.Martins,A.Gustchina,A.Wlodawer, I.Polikarpov

Key ref:

M.Sanches et al. (2007). Structural Characterization of B and non-B Subtypes of HIV-Protease: Insights into the Natural Susceptibility to Drug Resistance Development. J Mol Biol, 369, 1029-1040. PubMed id: 17467738 DOI: 10.1016/j.jmb.2007.03.049

Date:

08-Mar-07 Release date: 24-Apr-07

Protein chain

Q9Q2G8  (Q9Q2G8_9HIV1) -  V-1 protease (Fragment) from Human immunodeficiency virus 1

Seq: 99 a.a.

Struc: 99 a.a.*

Protein chain

Q9Q288  (Q9Q288_9HIV1) -  V-1 PROTEASE protein (Fragment) from Human immunodeficiency virus 1

Seq: 99 a.a.

Struc: 99 a.a.*

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

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.23.16 - HIV-1 retropepsin.
• Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.

DOI no: 10.1016/j.jmb.2007.03.049

J Mol Biol 369:1029-1040 (2007)

PubMed id: 17467738

Structural Characterization of B and non-B Subtypes of HIV-Protease: Insights into the Natural Susceptibility to Drug Resistance Development.

M.Sanches, S.Krauchenco, N.H.Martins, A.Gustchina, A.Wlodawer, I.Polikarpov.

ABSTRACT

Although a majority of HIV-1 infections in Brazil are caused by the subtype B virus (also prevalent in the United States and Western Europe), viral subtypes F and C are also found very frequently. Genomic differences between the subtypes give rise to sequence variations in the encoded proteins, including the HIV-1 protease. The current anti-HIV drugs have been developed primarily against subtype B and the effects arising from the combination of drug-resistance mutations with the naturally existing polymorphisms in non-B HIV-1 subtypes are only beginning to be elucidated. To gain more insights into the structure and function of different variants of HIV proteases, we have determined a 2.1 A structure of the native subtype F HIV-1 protease (PR) in complex with the protease inhibitor TL-3. We have also solved crystal structures of two multi-drug resistant mutant HIV PRs in complex with TL-3, from subtype B (Bmut) carrying the primary mutations V82A and L90M, and from subtype F (Fmut) carrying the primary mutation V82A plus the secondary mutation M36I, at 1.75 A and 2.8 A resolution, respectively. The proteases Bmut, Fwt and Fmut exhibit sevenfold, threefold, and 54-fold resistance to TL-3, respectively. In addition, the structure of subtype B wild type HIV-PR in complex with TL-3 has been redetermined in space group P6(1), consistent with the other three structures. Our results show that the primary mutation V82A causes the known effect of collapsing the S1/S1' pockets that ultimately lead to the reduced inhibitory effect of TL-3. Our results further indicate that two naturally occurring polymorphic substitutions in subtype F and other non-B HIV proteases, M36I and L89M, may lead to early development of drug resistance in patients infected with non-B HIV subtypes.

Selected figure(s)

Figure 2.

Figure 6.
Figure 6. Effects of the mutation V82A on the inhibitor-binding mode. The inhibitor subsite P1/P1′ is shown in ball-and-stick representation along with the pocket S1/S1′ in stick representation, for the structures Bwt (red) and Bmut (green). The broken lines represent hydrogen bonds between the active site aspartate residues and the oxygen of the diol in the center of the inhibitor, whereas the asterisks mark residues that belong to chain B. Due to the asymmetric mode of binding of the inhibitor, the S1′ pocket, occupied by the P1′ phenyl side-chain, accommodates one hydroxyl of the central diol, which is indicated by a dotted circle. Whereas there is no significant modification in the P1 subsite due to V82A mutation (marked with a square), in the P1′ a rotation of the Phe ring of the inhibitor is observed. This rotation decreases the number of interactions between the inhibitor's side-chain and the S1′ pocket, while the interactions are maintained in the S1 pocket.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 369, 1029-1040) copyright 2007.

Figures were selected by an automated process.