spacer
spacer

PDBsum entry 2r3c
Go to PDB code: 
protein metals Protein-protein interface(s) links
Viral protein/viral protein inhibitor PDB id
2r3c

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chains
47 a.a.
43 a.a.
15 a.a.
16 a.a.
Metals
_CL
YT3 ×5
Waters ×210
PDB id:
2r3c
Name: Viral protein/viral protein inhibitor
Title: Structure of the gp41 n-peptide in complex with the HIV entry inhibitor pie1
Structure: Gp41 n-peptide. Chain: a, b. Engineered: yes. HIV entry inhibitor pie1. Chain: c, d. Engineered: yes
Source: Synthetic: yes. Synthetic construct. Organism_taxid: 32630. Other_details: peptide synthesis. Other_details: peptide synthesis
Resolution:
1.73Å     R-factor:   0.193     R-free:   0.230
Authors: A.P.Vandemark,B.Welch,A.Heroux,C.P.Hill,M.S.Kay
Key ref:
B.D.Welch et al. (2007). Potent D-peptide inhibitors of HIV-1 entry. Proc Natl Acad Sci U S A, 104, 16828-16833. PubMed id: 17942675 DOI: 10.1073/pnas.0708109104
Date:
29-Aug-07     Release date:   02-Oct-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
No UniProt id for this chain
Struc: 46 a.a.
Protein chain
No UniProt id for this chain
Struc: 43 a.a.
Protein chain
No UniProt id for this chain
Struc: 15 a.a.
Protein chain
No UniProt id for this chain
Struc: 16 a.a.
Key:    Secondary structure  CATH domain

 

 
DOI no: 10.1073/pnas.0708109104 Proc Natl Acad Sci U S A 104:16828-16833 (2007)
PubMed id: 17942675  
 
 
Potent D-peptide inhibitors of HIV-1 entry.
B.D.Welch, A.P.VanDemark, A.Heroux, C.P.Hill, M.S.Kay.
 
  ABSTRACT  
 
During HIV-1 entry, the highly conserved gp41 N-trimer pocket region becomes transiently exposed and vulnerable to inhibition. Using mirror-image phage display and structure-assisted design, we have discovered protease-resistant D-amino acid peptides (D-peptides) that bind the N-trimer pocket with high affinity and potently inhibit viral entry. We also report high-resolution crystal structures of two of these D-peptides in complex with a pocket mimic that suggest sources of their high potency. A trimeric version of one of these peptides is the most potent pocket-specific entry inhibitor yet reported by three orders of magnitude (IC(50) = 250 pM). These results are the first demonstration that D-peptides can form specific and high-affinity interactions with natural protein targets and strengthen their promise as therapeutic agents. The D-peptides described here address limitations associated with current L-peptide entry inhibitors and are promising leads for the prevention and treatment of HIV/AIDS.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Structural analysis of the IQN17:2K-PIE1 inhibitor complex. (A) IQN17, consisting of IQ (orange) and gp41 (N17, gray) segments, with inhibitors (green, yellow, and purple) located in the canonical gp41 binding pockets. The purple inhibitor is mostly occluded in this view. (B) Omit map for 2K-PIE1 contoured at 3.0 x rmsd. Five of the eight pocket residues (gray, HXB2 numbering) that make hydrophobic contacts with 2K-PIE1 (green) are shown. Two hydrogen bonds (black) at the binding interface are also shown. (C) Overlay of D10-p1 (slate) and 2K-PIE1 (green) superposed by alignment of the IQN17 trimers. Intramolecular disulfide bonds (solid yellow) are also shown. (D) A slab view through the center of 2K-PIE1 (green) reveals an intact hydrophobic core (black) that excludes water. (E) A similar view of D10-p1 (slate) reveals the presence of several water molecules (red) in its core that nearly form a water channel. (F) End-on view of the complex (same color scheme as A) in which the surface from the last three residues of IQN17 have been removed. This view illustrates the packing of the inhibitor into the deep hydrophobic pocket. dK2 (blue), equivalent to the N-terminal Lys in PIE7 used for cross-linking, is highlighted. 		Figure 4.
Fig. 4. Structural analysis of the IQN17:2K-PIE1 and IQN17:PIE7 inhibitor complexes. Shown is a comparison of unique polar contacts observed in the 2K-PIE1 (A) and PIE7 (B) costructures (described in the text).
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21465559 L.T.Da, J.M.Quan, and Y.D.Wu (2011).
Understanding the binding mode and function of BMS-488043 against HIV-1 viral entry.
  Proteins, 79, 1810-1819.  
20230061 B.E.McGillick, T.E.Balius, S.Mukherjee, and R.C.Rizzo (2010).
Origins of resistance to the HIVgp41 viral entry inhibitor T20.
  Biochemistry, 49, 3575-3592.  
19966279 D.Roymans, H.L.De Bondt, E.Arnoult, P.Geluykens, T.Gevers, M.Van Ginderen, N.Verheyen, H.Kim, R.Willebrords, J.F.Bonfanti, W.Bruinzeel, M.D.Cummings, H.van Vlijmen, and K.Andries (2010).
Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein.
  Proc Natl Acad Sci U S A, 107, 308-313.
PDB code: 3kpe
20660316 G.H.Bird, N.Madani, A.F.Perry, A.M.Princiotto, J.G.Supko, X.He, E.Gavathiotis, J.G.Sodroski, and L.D.Walensky (2010).
Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic.
  Proc Natl Acad Sci U S A, 107, 14093-14098.  
20845360 L.Cai, and S.Jiang (2010).
Development of peptide and small-molecule HIV-1 fusion inhibitors that target gp41.
  ChemMedChem, 5, 1813-1824.  
20210752 M.L.Bellows, and C.A.Floudas (2010).
Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases.
  Curr Drug Targets, 11, 264-278.  
21081094 M.L.Bellows, M.S.Taylor, P.A.Cole, L.Shen, R.F.Siliciano, H.K.Fung, and C.A.Floudas (2010).
Discovery of entry inhibitors for HIV-1 via a new de novo protein design framework.
  Biophys J, 99, 3445-3453.  
20660730 M.Liu, C.Li, M.Pazgier, C.Li, Y.Mao, Y.Lv, B.Gu, G.Wei, W.Yuan, C.Zhan, W.Y.Lu, and W.Lu (2010).
D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms.
  Proc Natl Acad Sci U S A, 107, 14321-14326.
PDB code: 3iwy
20835389 S.P.Liu, L.Zhou, R.Lakshminarayanan, and R.W.Beuerman (2010).
Multivalent Antimicrobial Peptides as Therapeutics: Design Principles and Structural Diversities.
  Int J Pept Res Ther, 16, 199-213.  
19932616 Y.Wang, H.Lu, Q.Zhu, S.Jiang, and Y.Liao (2010).
Structure-based design, synthesis and biological evaluation of new N-carboxyphenylpyrrole derivatives as HIV fusion inhibitors targeting gp41.
  Bioorg Med Chem Lett, 20, 189-192.  
19497744 A.D.Bautista, O.M.Stephens, L.Wang, R.A.Domaoal, K.S.Anderson, and A.Schepartz (2009).
Identification of a beta3-peptide HIV fusion inhibitor with improved potency in live cells.
  Bioorg Med Chem Lett, 19, 3736-3738.  
19632107 F.Naider, and J.Anglister (2009).
Peptides in the treatment of AIDS.
  Curr Opin Struct Biol, 19, 473-482.  
19786602 H.Wang, Z.Qi, A.Guo, Q.Mao, H.Lu, X.An, C.Xia, X.Li, A.K.Debnath, S.Wu, S.Liu, and S.Jiang (2009).
ADS-J1 inhibits human immunodeficiency virus type 1 entry by interacting with the gp41 pocket region and blocking fusion-active gp41 core formation.
  Antimicrob Agents Chemother, 53, 4987-4998.  
19956769 K.M.Kahle, H.K.Steger, and M.J.Root (2009).
Asymmetric deactivation of HIV-1 gp41 following fusion inhibitor binding.
  PLoS Pathog, 5, e1000674.  
19297617 P.Ingallinella, E.Bianchi, N.A.Ladwa, Y.J.Wang, R.Hrin, M.Veneziano, F.Bonelli, T.J.Ketas, J.P.Moore, M.D.Miller, and A.Pessi (2009).
Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency.
  Proc Natl Acad Sci U S A, 106, 5801-5806.  
19254207 P.M.Colman (2009).
New antivirals and drug resistance.
  Annu Rev Biochem, 78, 95.  
19603110 S.A.Funke, and D.Willbold (2009).
Mirror image phage display--a method to generate D-peptide ligands for use in diagnostic or therapeutical applications.
  Mol Biosyst, 5, 783-786.  
19706443 W.S.Horne, L.M.Johnson, T.J.Ketas, P.J.Klasse, M.Lu, J.P.Moore, and S.H.Gellman (2009).
Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers.
  Proc Natl Acad Sci U S A, 106, 14751-14756.
PDB codes: 3f4y 3f4z 3f50 3g7a
18802030 D.M.Eckert, Y.Shi, S.Kim, B.D.Welch, E.Kang, E.S.Poff, and M.S.Kay (2008).
Characterization of the steric defense of the HIV-1 gp41 N-trimer region.
  Protein Sci, 17, 2091-2100.  
18499210 J.D.Nelson, H.Kinkead, F.M.Brunel, D.Leaman, R.Jensen, J.M.Louis, T.Maruyama, C.A.Bewley, K.Bowdish, G.M.Clore, P.E.Dawson, S.Frederickson, R.G.Mage, D.D.Richman, D.R.Burton, and M.B.Zwick (2008).
Antibody elicited against the gp41 N-heptad repeat (NHR) coiled-coil can neutralize HIV-1 with modest potency but non-neutralizing antibodies also bind to NHR mimetics.
  Virology, 377, 170-183.  
18568847 J.M.White, S.E.Delos, M.Brecher, and K.Schornberg (2008).
Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme.
  Crit Rev Biochem Mol Biol, 43, 189-219.  
  19094217 M.M.Lederman, R.Jump, H.A.Pilch-Cooper, M.Root, and S.F.Sieg (2008).
Topical application of entry inhibitors as "virustats" to prevent sexual transmission of HIV infection.
  Retrovirology, 5, 116.  
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.

 

spacer
spacer