Thermodynamics of Binding of a Low-Molecular-Weight CD4 Mimetic to HIV-1 gp120
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- 作者：Arne Schö ; n ; Navid Madani ; Jeffrey C. Klein ; Amy Hubicki ; Danny Ng ; Xinzhen Yang ; Amos B. Smith ; III ; Joseph Sodroski ; Ernesto Freire
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：September 12, 2006
- 年：2006
- 卷：45
- 期：36
- 页码：10973 - 10980
- 全文大小：254K
- 年卷期：v.45,no.36(September 12, 2006)
- ISSN：1520-4995
文摘
NBD-556 and the chemically and structurally similar NBD-557 are two low-molecular weightcompounds that reportedly block the interaction between the HIV-1 envelope glycoprotein gp120 and itsreceptor, CD4. NBD-556 binds to gp120 with a binding affinity of 2.7 × 105 M-1 (Kd = 3.7 
M) in aprocess characterized by a large favorable change in enthalpy partially compensated by a large unfavorableentropy change, a thermodynamic signature similar to that observed for binding of sCD4 to gp120. NBD-556 binding is associated with a large structuring of the gp120 molecule, as also demonstrated by CDspectroscopy. NBD-556, like CD4, activates the binding of gp120 to the HIV-1 coreceptor, CCR5, andto the 17b monoclonal antibody, which recognizes the coreceptor binding site of gp120. NBD-556 stimulatesHIV-1 infection of CD4-negative, CCR5-expressing cells. The thermodynamic signature of the bindingof NBD-556 to gp120 is very different from that of another viral entry inhibitor, BMS-378806. WhereasNBD-556 binds gp120 with a large favorable enthalpy and compensating unfavorable entropy changes,BMS-378806 does so with a small binding enthalpy change in a mostly entropy-driven process. NBD-556 is a competitive inhibitor of sCD4 and elicits a similar structuring of the coreceptor binding site,whereas BMS-378806 does not compete with sCD4 and does not induce coreceptor binding. These studiesdemonstrate that low-molecular-weight compounds can induce conformational changes in the HIV-1 gp120glycoprotein similar to those observed upon CD4 binding, revealing distinct strategies for inhibiting thefunction of the HIV-1 gp120 envelope glycoprotein. Furthermore, competitive and noncompetitivecompounds have characteristic thermodynamic signatures that can be used to guide the design of morepotent and effective viral entry inhibitors.
M) in aprocess characterized by a large favorable change in enthalpy partially compensated by a large unfavorableentropy change, a thermodynamic signature similar to that observed for binding of sCD4 to gp120. NBD-556 binding is associated with a large structuring of the gp120 molecule, as also demonstrated by CDspectroscopy. NBD-556, like CD4, activates the binding of gp120 to the HIV-1 coreceptor, CCR5, andto the 17b monoclonal antibody, which recognizes the coreceptor binding site of gp120. NBD-556 stimulatesHIV-1 infection of CD4-negative, CCR5-expressing cells. The thermodynamic signature of the bindingof NBD-556 to gp120 is very different from that of another viral entry inhibitor, BMS-378806. WhereasNBD-556 binds gp120 with a large favorable enthalpy and compensating unfavorable entropy changes,BMS-378806 does so with a small binding enthalpy change in a mostly entropy-driven process. NBD-556 is a competitive inhibitor of sCD4 and elicits a similar structuring of the coreceptor binding site,whereas BMS-378806 does not compete with sCD4 and does not induce coreceptor binding. These studiesdemonstrate that low-molecular-weight compounds can induce conformational changes in the HIV-1 gp120glycoprotein similar to those observed upon CD4 binding, revealing distinct strategies for inhibiting thefunction of the HIV-1 gp120 envelope glycoprotein. Furthermore, competitive and noncompetitivecompounds have characteristic thermodynamic signatures that can be used to guide the design of morepotent and effective viral entry inhibitors.