Linked Life Data

11551942

Source:http://linkedlifedata.com/resource/pubmed/id/11551942

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
46
pubmed:dateCreated
2001-11-12
pubmed:abstractText
The human CXC chemokine receptor 4 (CXCR4) is a receptor for the chemokine stromal cell-derived factor (SDF-1alpha) and a co-receptor for the entry of specific strains of human immunodeficiency virus type I (HIV-1). CXCR4 is also recognized by an antagonistic chemokine, the viral macrophage inflammatory protein II (vMIP-II) encoded by human herpesvirus type VIII. SDF-1alpha or vMIP-II binding to CXCR4 can inhibit HIV-1 entry via this co-receptor. An approach combining protein structural modeling and site-directed mutagenesis was used to probe the structure-function relationship of CXCR4, and interactions with its ligands SDF-1alpha and vMIP-II and HIV-1 envelope protein gp120. Hypothetical three-dimensional structures were proposed by molecular modeling studies of the CXCR4.SDF-1alpha complex, which rationalize extensive biological information on the role of CXCR4 in its interactions with HIV-1 envelope protein gp120. With site-directed mutagenesis, we have identified that the amino acid residues Asp (D20A) and Tyr (Y21A) in the N-terminal domain and the residue Glu (E268A) in extracellular loop 3 (ECL3) are involved in ligand binding, whereas the mutation Y190A in extracellular loop 2 (ECL2) impairs the signaling mediated by SDF-1alpha. As an HIV-1 co-receptor, we found that the N-terminal domain, ECL2, and ECL3 of CXCR4 are involved in HIV-1 entry. These structural and mutational studies provide valuable information regarding the structural basis for CXCR4 activity in chemokine binding and HIV-1 viral entry, and could guide the design of novel targeted inhibitors.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
16
pubmed:volume
276
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
42826-33
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11551942-Aspartic Acid, pubmed-meshheading:11551942-Calcium, pubmed-meshheading:11551942-Cell Line, pubmed-meshheading:11551942-Chemokines, pubmed-meshheading:11551942-Flow Cytometry, pubmed-meshheading:11551942-Genes, Reporter, pubmed-meshheading:11551942-Glutamic Acid, pubmed-meshheading:11551942-HIV-1, pubmed-meshheading:11551942-Humans, pubmed-meshheading:11551942-Ligands, pubmed-meshheading:11551942-Models, Molecular, pubmed-meshheading:11551942-Mutagenesis, Site-Directed, pubmed-meshheading:11551942-Mutation, pubmed-meshheading:11551942-Plasmids, pubmed-meshheading:11551942-Protein Binding, pubmed-meshheading:11551942-Protein Conformation, pubmed-meshheading:11551942-Protein Structure, Secondary, pubmed-meshheading:11551942-Protein Structure, Tertiary, pubmed-meshheading:11551942-Receptors, CXCR4, pubmed-meshheading:11551942-Recombinant Fusion Proteins, pubmed-meshheading:11551942-Recombinant Proteins, pubmed-meshheading:11551942-Signal Transduction, pubmed-meshheading:11551942-Structure-Activity Relationship, pubmed-meshheading:11551942-Tyrosine
pubmed:year
2001
pubmed:articleTitle
Structural and functional characterization of human CXCR4 as a chemokine receptor and HIV-1 co-receptor by mutagenesis and molecular modeling studies.
pubmed:affiliation
Kimmel Cancer Center, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.