PDBsum entry 1n49

Hydrolase/hydrolase inhibitor

PDB id

1n49

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Contents

			Protein chains

					99 a.a. *

			Ligands

					RIT ×2

			Waters ×28

* Residue conservation analysis

PDB id:

1n49

Links

Name:

Hydrolase/hydrolase inhibitor

Title:

Viability of a drug-resistant HIV-1 protease variant: structural insights for better anti-viral therapy

Structure:

Protease. Chain: a, b, c, d. Synonym: retropepsin. Engineered: yes. Mutation: yes

Source:

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

Biol. unit:

Dimer (from PQS)

Resolution:

2.20Å

R-factor:

0.223

R-free:

0.284

Authors:

M.Prabu-Jeyabalan,E.A.Nalivaika,N.M.King,C.A.Schiffer

Key ref:

M.Prabu-Jeyabalan et al. (2003). Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy. J Virol, 77, 1306-1315. PubMed id: 12502847

Date:

30-Oct-02

Release date:

07-Jan-03

PROCHECK

	Headers

	References

Protein chains

P03369 (POL_HV1A2) - Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2)

Seq: Struc:

Seq: Struc:

Seq: Struc:					1437 a.a. 99 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

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



		Enzyme reactions

Enzyme class 1:

E.C.2.7.7.- - ?????

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

Enzyme class 2:

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 3:

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 4:

E.C.3.1.-.-

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

Enzyme class 5:

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 6:

E.C.3.1.26.13 - retroviral ribonuclease H.

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

Enzyme class 7:

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

	J Virol 77:1306-1315 (2003)
PubMed id: 12502847

Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.
M.Prabu-Jeyabalan, E.A.Nalivaika, N.M.King, C.A.Schiffer.

ABSTRACT

Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21266017

A.S.Reddy, V.Jalahalli, S.Kumar, R.Garg, X.Zhang, and G.N.Sastry (2011).
Analysis of HIV protease binding pockets based on 3D shape and electrostatic potential descriptors.

Chem Biol Drug Des, 77, 137-151.

20490879

J.P.Yesudas, F.B.Sayyed, and C.H.Suresh (2011).
Analysis of structural water and CH···π interactions in HIV-1 protease and PTP1B complexes using a hydrogen bond prediction tool, HBPredicT.

J Mol Model, 17, 401-413.

20715057

S.K.Sadiq, and G.De Fabritiis (2010).
Explicit solvent dynamics and energetics of HIV-1 protease flap opening and closing.

Proteins, 78, 2873-2885.

20543885

Y.Cai, and C.A.Schiffer (2010).
Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV.

J Chem Theory Comput, 6, 1358-1368.

19254207

P.M.Colman (2009).
New antivirals and drug resistance.

Annu Rev Biochem, 78, 95.

18704947

S.Bihani, A.Das, V.Prashar, J.L.Ferrer, and M.V.Hosur (2009).
X-ray structure of HIV-1 protease in situ product complex.

Proteins, 74, 594-602.

PDB code:

3dox

18820715

E.Lefebvre, and C.A.Schiffer (2008).
Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir.

AIDS Rev, 10, 131-142.

17729291

M.D.Altman, E.A.Nalivaika, M.Prabu-Jeyabalan, C.A.Schiffer, and B.Tidor (2008).
Computational design and experimental study of tighter binding peptides to an inactivated mutant of HIV-1 protease.

Proteins, 70, 678-694.

PDB codes:

2nxd 2nxl 2nxm

19373036

M.N.Nalam, and C.A.Schiffer (2008).
New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors.

Curr Opin HIV AIDS, 3, 642-646.

18052235

A.Y.Kovalevsky, A.A.Chumanevich, F.Liu, J.M.Louis, and I.T.Weber (2007).
Caught in the Act: the 1.5 A resolution crystal structures of the HIV-1 protease and the I54V mutant reveal a tetrahedral reaction intermediate.

Biochemistry, 46, 14854-14864.

PDB codes:

3b7v 3b80

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

17642513

H.Heaslet, R.Rosenfeld, M.Giffin, Y.C.Lin, K.Tam, B.E.Torbett, J.H.Elder, D.E.McRee, and C.D.Stout (2007).
Conformational flexibility in the flap domains of ligand-free HIV protease.

Acta Crystallogr D Biol Crystallogr, 63, 866-875.

PDB codes:

2hb2 2hb4 2pc0

17596316

M.N.Nalam, A.Peeters, T.H.Jonckers, I.Dierynck, and C.A.Schiffer (2007).
Crystal structure of lysine sulfonamide inhibitor reveals the displacement of the conserved flap water molecule in human immunodeficiency virus type 1 protease.

J Virol, 81, 9512-9518.

PDB code:

2q3k

17539822

S.Chellappan, G.S.Kiran Kumar Reddy, A.Ali, M.N.Nalam, S.G.Anjum, H.Cao, V.Kairys, M.X.Fernandes, M.D.Altman, B.Tidor, T.M.Rana, C.A.Schiffer, and M.K.Gilson (2007).
Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis.

Chem Biol Drug Des, 69, 298-313.

PDB codes:

2psu 2psv

17474129

S.Chellappan, V.Kairys, M.X.Fernandes, C.Schiffer, and M.K.Gilson (2007).
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease.

Proteins, 68, 561-567.

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

16809296

J.E.Foulkes, M.Prabu-Jeyabalan, D.Cooper, G.J.Henderson, J.Harris, R.Swanstrom, and C.A.Schiffer (2006).
Role of invariant Thr80 in human immunodeficiency virus type 1 protease structure, function, and viral infectivity.

J Virol, 80, 6906-6916.

PDB codes:

2fgu 2fgv

16537628

M.Prabu-Jeyabalan, E.A.Nalivaika, K.Romano, and C.A.Schiffer (2006).
Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate.

J Virol, 80, 3607-3616.

PDB codes:

2fns 2fnt

16569872

M.Prabu-Jeyabalan, N.M.King, E.A.Nalivaika, G.Heilek-Snyder, N.Cammack, and C.A.Schiffer (2006).
Substrate envelope and drug resistance: crystal structure of RO1 in complex with wild-type human immunodeficiency virus type 1 protease.

Antimicrob Agents Chemother, 50, 1518-1521.

PDB code:

2f3k

15613309

F.Bouchonnet, E.Dam, F.Mammano, V.de Soultrait, G.Henneré, H.Benech, F.Clavel, and A.J.Hance (2005).
Quantification of the effects on viral DNA synthesis of reverse transcriptase mutations conferring human immunodeficiency virus type 1 resistance to nucleoside analogues.

J Virol, 79, 812-822.

15780884

K.Gendron, D.Dulude, G.Lemay, G.Ferbeyre, and L.Brakier-Gingras (2005).
The virion-associated Gag-Pol is decreased in chimeric Moloney murine leukemia viruses in which the readthrough region is replaced by the frameshift region of the human immunodeficiency virus type 1.

Virology, 334, 342-352.

15542562

K.Wittayanarakul, O.Aruksakunwong, S.Saen-oon, W.Chantratita, V.Parasuk, P.Sompornpisut, and S.Hannongbua (2005).
Insights into saquinavir resistance in the G48V HIV-1 protease: quantum calculations and molecular dynamic simulations.

Biophys J, 88, 867-879.

16338417

P.Martin, J.F.Vickrey, G.Proteasa, Y.L.Jimenez, Z.Wawrzak, M.A.Winters, T.C.Merigan, and L.C.Kovari (2005).
"Wide-open" 1.3 A structure of a multidrug-resistant HIV-1 protease as a drug target.

Structure, 13, 1887-1895.

PDB code:

1tw7

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

14990731

B.C.Logsdon, J.F.Vickrey, P.Martin, G.Proteasa, J.I.Koepke, S.R.Terlecky, Z.Wawrzak, M.A.Winters, T.C.Merigan, and L.C.Kovari (2004).
Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity.

J Virol, 78, 3123-3132.

PDB codes:

1rpi 1rq9 1rv7

15066177

B.Mahalingam, Y.F.Wang, P.I.Boross, J.Tozser, J.M.Louis, R.W.Harrison, and I.T.Weber (2004).
Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site.

Eur J Biochem, 271, 1516-1524.

PDB codes:

1sdt 1sdu 1sdv

15047838

C.Charpentier, D.E.Dwyer, F.Mammano, D.Lecossier, F.Clavel, and A.J.Hance (2004).
Role of minority populations of human immunodeficiency virus type 1 in the evolution of viral resistance to protease inhibitors.

J Virol, 78, 4234-4247.

15507631

M.Prabu-Jeyabalan, E.A.Nalivaika, N.M.King, and C.A.Schiffer (2004).
Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease.

J Virol, 78, 12446-12454.

PDB codes:

1tsq 1tsu

15489160

N.M.King, M.Prabu-Jeyabalan, E.A.Nalivaika, and C.A.Schiffer (2004).
Combating susceptibility to drug resistance: lessons from HIV-1 protease.

Chem Biol, 11, 1333-1338.

15479840

N.M.King, M.Prabu-Jeyabalan, E.A.Nalivaika, P.Wigerinck, M.P.de Béthune, and C.A.Schiffer (2004).
Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor.

J Virol, 78, 12012-12021.

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 code is shown on the right.