PDBsum entry 1sdt

Hydrolase

PDB id

1sdt

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Contents

			Protein chains

					99 a.a. *

			Ligands

					MK1

			Metals

					_CL ×2

			Waters ×170

* Residue conservation analysis

PDB id:

1sdt

Links

Name:

Hydrolase

Title:

Crystal structures of HIV protease v82a and l90m mutants reveal changes in indinavir binding site.

Structure:

Protease retropepsin. Chain: a, b. Synonym: HIV-1 protease. Engineered: yes. Other_details: complexed with indinavir

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: gag-pol. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

1.30Å

R-factor:

0.155

R-free:

0.190

Authors:

B.Mahalingam,Y.-F.Wang,P.I.Boross,J.Tozser,J.M.Louis,R.W.Harrison, I.T.Weber

Key ref:

B.Mahalingam et al. (2004). Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site. Eur J Biochem, 271, 1516-1524. PubMed id: 15066177 DOI: 10.1111/j.1432-1033.2004.04060.x

Date:

14-Feb-04

Release date:

25-May-04

PROCHECK

	Headers

	References

Protein chains

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

Seq: Struc:

Seq: Struc:

Seq: Struc:					1447 a.a. 99 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 5 residue positions (black crosses)



		Enzyme reactions

Enzyme class 1:

E.C.2.7.7.49 - RNA-directed Dna polymerase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate

DNA(n)	+	2'-deoxyribonucleoside 5'-triphosphate	=	DNA(n+1)	+	diphosphate

Enzyme class 2:

E.C.2.7.7.7 - DNA-directed Dna polymerase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate

DNA(n)	+	2'-deoxyribonucleoside 5'-triphosphate	=	DNA(n+1)	+	diphosphate

Enzyme class 3:

E.C.3.1.13.2 - exoribonuclease H.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

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.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Enzyme class 5:

E.C.3.4.23.16 - HIV-1 retropepsin.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

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: 10.1111/j.1432-1033.2004.04060.x	Eur J Biochem 271:1516-1524 (2004)
PubMed id: 15066177

Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site.
B.Mahalingam, Y.F.Wang, P.I.Boross, J.Tozser, J.M.Louis, R.W.Harrison, I.T.Weber.

ABSTRACT

The crystal structures of the wild-type HIV-1 protease (PR) and the two resistant variants, PR(V82A) and PR(L90M), have been determined in complex with the antiviral drug, indinavir, to gain insight into the molecular basis of drug resistance. V82A and L90M correspond to an active site mutation and nonactive site mutation, respectively. The inhibition (K(i)) of PR(V82A) and PR(L90M) was 3.3- and 0.16-fold, respectively, relative to the value for PR. They showed only a modest decrease, of 10-15%, in their k(cat)/K(m) values relative to PR. The crystal structures were refined to resolutions of 1.25-1.4 A to reveal critical features associated with inhibitor resistance. PR(V82A) showed local changes in residues 81-82 at the site of the mutation, while PR(L90M) showed local changes near Met90 and an additional interaction with indinavir. These structural differences concur with the kinetic data.

Selected figure(s)



	Figure 3. Fig. 3. Interaction of Met90'and Asp25' in PR[L90M]. (A) The 2Fo–Fc electron density map showing Met90', Asp25' and Thr26'in the PR[L90M] structure. The side chain of Met90' has two conformations, and one conformation has a short separation from the carbonyl oxygen of the catalytic Asp25'. (B) Comparison of Met90' in PR[L90M] and Leu90' in the wild-type HIV-1 protease (PR) relative to Asp25'. The PR residues are in black and the PR[L90M] residues are in gray. Hydrogen bonds are indicated by dashed lines, with the distances shown in Å.		Figure 6. Fig. 6. Structural variation in residues 81–82 near indinavir. Stereoview showing the benzyl group of indinavir interacting with residues 81–82, using the major conformation of Val82. The wild-type HIV-1 protease (PR) structure is in black and the mutant is in gray bonds. Interatomic distances are given in Å. (A) PR[V82A] superimposed on PR. (B) PR[L90M] superimposed on PR.

Figures were selected by an automated process.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21465560

S.Karthik, and S.Senapati (2011).
Dynamic flaps in HIV-1 protease adopt unique ordering at different stages in the catalytic cycle.

Proteins, 79, 1830-1840.

20695887

C.H.Shen, Y.F.Wang, A.Y.Kovalevsky, R.W.Harrison, and I.T.Weber (2010).
Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters.

FEBS J, 277, 3699-3714.

PDB codes:

3nu3 3nu4 3nu5 3nu6 3nu9 3nuj 3nuo

20080674

J.Zhang, T.Hou, W.Wang, and J.S.Liu (2010).
Detecting and understanding combinatorial mutation patterns responsible for HIV drug resistance.

Proc Natl Acad Sci U S A, 107, 1321-1326.

19928916

D.Das, Y.Koh, Y.Tojo, A.K.Ghosh, and H.Mitsuya (2009).
Prediction of potency of protease inhibitors using free energy simulations with polarizable quantum mechanics-based ligand charges and a hybrid water model.

J Chem Inf Model, 49, 2851-2862.

18833280

C.Tang, J.M.Louis, A.Aniana, J.Y.Suh, and G.M.Clore (2008).
Visualizing transient events in amino-terminal autoprocessing of HIV-1 protease.

Nature, 455, 693-696.

18281688

J.M.Sayer, F.Liu, R.Ishima, I.T.Weber, and J.M.Louis (2008).
Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease.

J Biol Chem, 283, 13459-13470.

PDB codes:

3bva 3bvb

17854027

C.Garriga, M.J.Pérez-Elías, R.Delgado, L.Ruiz, R.Nájera, T.Pumarola, M.d.e.l. .M.Alonso-Socas, S.García-Bujalance, and L.Menéndez-Arias (2007).
Mutational patterns and correlated amino acid substitutions in the HIV-1 protease after virological failure to nelfinavir- and lopinavir/ritonavir-based treatments.

J Med Virol, 79, 1617-1628.

17537865

H.E.Klei, K.Kish, P.F.Lin, Q.Guo, J.Friborg, R.E.Rose, Y.Zhang, V.Goldfarb, D.R.Langley, M.Wittekind, and S.Sheriff (2007).
X-ray crystal structures of human immunodeficiency virus type 1 protease mutants complexed with atazanavir.

J Virol, 81, 9525-9535.

PDB codes:

2fxd 2fxe

17401206

R.M.Coman, A.Robbins, M.M.Goodenow, R.McKenna, and B.M.Dunn (2007).
Expression, purification and preliminary X-ray crystallographic studies of the human immunodeficiency virus 1 subtype C protease.

Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 320-323.

17696515

Y.F.Wang, Y.Tie, P.I.Boross, J.Tozser, A.K.Ghosh, R.W.Harrison, and I.T.Weber (2007).
Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease.

J Med Chem, 50, 4509-4515.

PDB codes:

2qci 2qd6 2qd7 2qd8 2z4o

17243183

Y.Tie, A.Y.Kovalevsky, P.Boross, Y.F.Wang, A.K.Ghosh, J.Tozser, R.W.Harrison, and I.T.Weber (2007).
Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir.

Proteins, 67, 232-242.

PDB codes:

2nmw 2nmy 2nmz 2nnk 2nnp 3oxc

16962136

A.Y.Kovalevsky, F.Liu, S.Leshchenko, A.K.Ghosh, J.M.Louis, R.W.Harrison, and I.T.Weber (2006).
Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114.

J Mol Biol, 363, 161-173.

PDB codes:

2hs1 2hs2

16480273

A.Y.Kovalevsky, Y.Tie, F.Liu, P.I.Boross, Y.F.Wang, S.Leshchenko, A.K.Ghosh, R.W.Harrison, and I.T.Weber (2006).
Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M.

J Med Chem, 49, 1379-1387.

PDB codes:

2f80 2f81 2f8g

16277992

F.Liu, P.I.Boross, Y.F.Wang, J.Tozser, J.M.Louis, R.W.Harrison, and I.T.Weber (2005).
Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S.

J Mol Biol, 354, 789-800.

PDB codes:

2avm 2avo 2avq 2avs 2avv

16218957

Y.Tie, P.I.Boross, Y.F.Wang, L.Gaddis, F.Liu, X.Chen, J.Tozser, R.W.Harrison, and I.T.Weber (2005).
Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 angstroms resolution crystal structures of HIV-1 protease mutants with substrate analogs.

FEBS J, 272, 5265-5277.

PDB codes:

2aoc 2aod 2aoe 2aof 2aog 2aoh 2aoi 2aoj

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.