PDBsum entry 1c1c

Transferase

PDB id

1c1c

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Contents

			Protein chains

					537 a.a. *


					416 a.a. *

			Ligands

					612

			Waters ×142

* Residue conservation analysis

PDB id:

1c1c

Links

Name:

Transferase

Title:

Crystal structure of HIV-1 reverse transcriptase in complex with tnk- 6123

Structure:

HIV-1 reverse transcriptase (a-chain). Chain: a. Fragment: p66. Engineered: yes. HIV-1 reverse transcriptase (b-chain). Chain: b. Fragment: p51. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: hxb2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

2.50Å

R-factor:

0.232

R-free:

0.315

Authors:

A.L.Hopkins,J.Ren,H.Tanaka,M.Baba,M.Okamato,D.I.Stuart,D.K.Stammers

Key ref:

A.L.Hopkins et al. (1999). Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants. J Med Chem, 42, 4500-4505. PubMed id: 10579814 DOI: 10.1021/jm990192c

Date:

21-Jul-99

Release date:

21-Jul-00

PROCHECK

	Headers

	References

Protein chain

P04585 (POL_HV1H2) - Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: Struc:

Seq: Struc:

Seq: Struc:					1435 a.a. 537 a.a.*

Protein chain

P04585 (POL_HV1H2) - Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: Struc:

Seq: Struc:

Seq: Struc:					1435 a.a. 416 a.a.

Key:

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 1 residue position (black cross)



		Enzyme reactions

Enzyme class 1:

Chains A, B: E.C.2.7.7.- - ?????

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

Enzyme class 2:

Chains A, B: 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:

Chains A, B: 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:

Chains A, B: E.C.3.1.-.-

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

Enzyme class 5:

Chains A, B: 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:

Chains A, B: E.C.3.1.26.13 - retroviral ribonuclease H.

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

Enzyme class 7:

Chains A, B: 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: 10.1021/jm990192c	J Med Chem 42:4500-4505 (1999)
PubMed id: 10579814

Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants.
A.L.Hopkins, J.Ren, H.Tanaka, M.Baba, M.Okamato, D.I.Stuart, D.K.Stammers.

ABSTRACT

Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.

Literature references that cite this PDB file's key reference

PubMed id

Reference

22719549

N.R.El-Brollosy, M.I.Attia, A.A.El-Emam, S.W.Ng, and E.R.Tiekink (2012).
6-Methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]-oxy}meth-yl)-1,2,3,4-tetra-hydro-quinazoline-2,4-dione.

Acta Crystallogr Sect E Struct Rep Online, 68, o1768-o1769.

22719550

N.R.El-Brollosy, M.I.Attia, A.A.El-Emam, S.W.Ng, and E.R.Tiekink (2012).
6-Chloro-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]-oxy}meth-yl)-1,2,3,4-tetra-hydro-quinazoline-2,4-dione.

Acta Crystallogr Sect E Struct Rep Online, 68, o1770-o1771.

22589903

N.R.El-Brollosy, M.I.Attia, H.A.Ghabbour, S.Chantrapromma, and H.K.Fun (2012).
6-(3,5-Dimethyl-benz-yl)-5-ethyl-1-[(2-phenyl-eth-oxy)meth-yl]pyrimidine-2,4(1H,3H)dione.

Acta Crystallogr Sect E Struct Rep Online, 68, o1031-o1032.

22719629

N.R.El-Brollosy, N.Dege, G.Demirtaş, M.I.Attia, A.A.El-Emam, and O.Büyükgüngör (2012).
1-{[(2,3-Dihydro-1H-inden-2-yl)-oxy]meth-yl}quinazoline-2,4(1H,3H)-dione.

Acta Crystallogr Sect E Struct Rep Online, 68, o1866-o1867.

21392991

J.Tang, K.Maddali, C.D.Dreis, Y.Y.Sham, R.Vince, Y.Pommier, and Z.Wang (2011).
6-Benzoyl-3-hydroxypyrimidine-2,4-diones as dual inhibitors of HIV reverse transcriptase and integrase.

Bioorg Med Chem Lett, 21, 2400-2402.

19856332

N.R.El-Brollosy, O.A.Al-Deeb, A.A.El-Emam, E.B.Pedersen, P.La Colla, G.Collu, G.Sanna, and R.Loddo (2009).
Synthesis of novel uracil non-nucleoside derivatives as potential reverse transcriptase inhibitors of HIV-1.

Arch Pharm (Weinheim), 342, 663-670.

18217215

R.D.Clark (2008).
A ligand's-eye view of protein binding.

J Comput Aided Mol Des, 22, 507-521.

17477343

J.L.Medina-Franco, K.Martínez-Mayorga, C.Juárez-Gordiano, and R.Castillo (2007).
Pyridin-2(1H)-ones: A Promising Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors.

ChemMedChem, 2, 1141-1147.

16911530

J.Ren, C.E.Nichols, A.Stamp, P.P.Chamberlain, R.Ferris, K.L.Weaver, S.A.Short, and D.K.Stammers (2006).
Structural insights into mechanisms of non-nucleoside drug resistance for HIV-1 reverse transcriptases mutated at codons 101 or 138.

FEBS J, 273, 3850-3860.

PDB codes:

2hnd 2hny 2hnz

17036113

X.Wang, Q.Lou, Y.Guo, Y.Xu, Z.Zhang, and J.Liu (2006).
The design and synthesis of 9-phenylcyclohepta[d]pyrimidine-2,4-dione derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase.

Org Biomol Chem, 4, 3252-3258.

15996003

E.R.Sørensen, N.R.El-Brollosy, P.T.Jørgensen, E.B.Pedersen, and C.Nielsen (2005).
Synthesis of 6-(3,5-dichlorobenzyl) derivatives as isosteric analogues of the HIV drug 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil (GCA-186).

Arch Pharm (Weinheim), 338, 299-304.

16079514

G.F.Sun, X.X.Chen, F.E.Chen, Y.P.Wang, E.De Clercq, J.Balzarini, and C.Pannecouque (2005).
Nonnucleoside HIV-1 reverse-transcriptase inhibitors, part 5. Synthesis and anti-HIV-1 activity of novel 6-naphthylthio HEPT analogues.

Chem Pharm Bull (Tokyo), 53, 886-892.

15016861

E.N.Peletskaya, A.A.Kogon, S.Tuske, E.Arnold, and S.H.Hughes (2004).
Nonnucleoside inhibitor binding affects the interactions of the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase with DNA.

J Virol, 78, 3387-3397.

PDB code:

1r0a

14748000

F.Daeyaert, M.de Jonge, J.Heeres, L.Koymans, P.Lewi, M.H.Vinkers, and P.A.Janssen (2004).
A pharmacophore docking algorithm and its application to the cross-docking of 18 HIV-NNRTI's in their binding pockets.

Proteins, 54, 526-533.

15249669

J.D.Pata, W.G.Stirtan, S.W.Goldstein, and T.A.Steitz (2004).
Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors.

Proc Natl Acad Sci U S A, 101, 10548-10553.

PDB code:

1tv6

15229890

M.Barbany, H.Gutiérrez-de-Terán, F.Sanz, and J.Villà-Freixa (2004).
Towards a MIP-based alignment and docking in computer-aided drug design.

Proteins, 56, 585-594.

12843582

G.Meng, F.E.Chen, E.De Clercq, J.Balzarini, and C.Pannecouque (2003).
Nonnucleoside HIV-1 reverse transcriptase inhibitors: Part I. Synthesis and structure-activity relationship of 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils as HEPT analogues.

Chem Pharm Bull (Tokyo), 51, 779-789.

12369088

E.De Clercq (2002).
New anti-HIV agents and targets.

Med Res Rev, 22, 531-565.

11533206

E.N.Peletskaya, P.L.Boyer, A.A.Kogon, P.Clark, H.Kroth, J.M.Sayer, D.M.Jerina, and S.H.Hughes (2001).
Cross-linking of the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase to template-primer.

J Virol, 75, 9435-9445.

10799511

J.Ren, C.Nichols, L.E.Bird, T.Fujiwara, H.Sugimoto, D.I.Stuart, and D.K.Stammers (2000).
Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding.

J Biol Chem, 275, 14316-14320.

PDB code:

1ep4

10681546

J.Ren, J.Diprose, J.Warren, R.M.Esnouf, L.E.Bird, S.Ikemizu, M.Slater, J.Milton, J.Balzarini, D.I.Stuart, and D.K.Stammers (2000).
Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses.

J Biol Chem, 275, 5633-5639.

PDB codes:

1dtq 1dtt

11080630

J.Ren, J.Milton, K.L.Weaver, S.A.Short, D.I.Stuart, and D.K.Stammers (2000).
Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase.

Structure, 8, 1089-1094.

PDB codes:

1fk9 1fko 1fkp

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.