Theoretical Model for HIV-1 PR That Accounts for Substrate Recognition and Preferential Cleavage of Natural Substrates

2019 ◽  
Vol 123 (30) ◽  
pp. 6389-6400 ◽  
Author(s):  
Zainab K. Sanusi ◽  
Monsurat M. Lawal ◽  
Thavendran Govender ◽  
Glenn E. M. Maguire ◽  
Bahareh Honarparvar ◽  
...  
Keyword(s):  
Theoretical Model ◽  
Substrate Recognition ◽  
Preferential Cleavage ◽  
Hiv 1

Substrate Recognition in HIV-1 Protease: A Computational Study

2010 ◽  
Vol 114 (7) ◽  
pp. 2525-2532 ◽  
Author(s):  
M. A. S. Perez ◽  
P. A. Fernandes ◽  
M. J. Ramos
Keyword(s):  
Computational Study ◽  
Substrate Recognition ◽  
Hiv 1

scholarly journals Mechanism of Substrate Recognition by Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variants Revealed by a Novel Structural Intermediate

2006 ◽  
Vol 80 (7) ◽  
pp. 3607-3616 ◽  
Author(s):  
Moses Prabu-Jeyabalan ◽  
Ellen A. Nalivaika ◽  
Keith Romano ◽  
Celia A. Schiffer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Crystal Structures ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Structural Model ◽  
Substrate Recognition ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Ligand binding occurs when the flaps open, allowing access to the active site. This flexibility in flap geometry makes trapping and crystallizing structural intermediates in substrate binding challenging. In this study, we report two crystal structures of two HIV-1 protease variants bound with their corresponding nucleocapsid-p1 variant. One of the flaps in each of these structures exhibits an unusual “intermediate” conformation. Analysis of the flap-intermediate and flap-closed crystal structures reveals that the intermonomer flap movements may be asynchronous and that the flap which wraps over the P3 to P1 (P3-P1) residues of the substrate might close first. This is consistent with our hypothesis that the P3-P1 region is crucial for substrate recognition. The intermediate conformation is conserved in both the wild-type and drug-resistant variants. The structural differences between the variants are evident only when the flaps are closed. Thus, a plausible structural model for the adaptability of HIV-1 protease to recognize substrates in the presence of drug-resistant mutations has been proposed.

Combatting Drug Resistance: Lessons from the viral proteases of HIV and HCV

2014 ◽  
Vol 70 (a1) ◽  
pp. C116-C116
Author(s):  
Celia Schiffer
Keyword(s):  
Drug Resistance ◽  
Hepatitis C ◽  
Biological Function ◽  
Substrate Recognition ◽  
Atomic Resolution ◽  
Inhibitor Binding ◽  
Detailed Understanding ◽  
Viral Proteases ◽  
Hiv 1 ◽  
Substrate Envelope

Drug resistance negatively impacts the lives of millions of patients and costs our society billions of dollars by limiting the longevity of many of our most potent drugs. Drug resistance can be caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the target. To reduce the likelihood of drug resistance, a detailed understanding of the target's function is necessary. Both structure at atomic resolution and evolutionarily constraints on its variation is required. "Resilient" targets are less susceptible to drug resistance due to their key location in a particular pathway. This rationale was derived through crystallographic studies elucidating substrate recognition and drug resistance in HIV-1 protease and Hepatitis C (HCV) NS3/4A protease. Both are key therapeutic targets and are potentially "resilient" targets where resistant mutations occur outside of the substrate binding site. To reduce the probability of drug resistance inhibitors should be designed to fit within what we define as the "substrate envelope". These principals are likely more generally applicable to other quickly evolving diseases where drug resistance is quickly evolving. http://www.umassmed.edu/schifferlab/index.aspx

scholarly journals Using Molecular Dynamics to Investigate Substrate Recognition and Co-evolution in HIV-1 Protease

2009 ◽  
Vol 96 (3) ◽  
pp. 598a
Author(s):  
Aysegul Ozen ◽  
Turkan Haliloglu ◽  
Celia A. Schiffer
Keyword(s):  
Molecular Dynamics ◽  
Substrate Recognition ◽  
Hiv 1

scholarly journals Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 A resolution crystal structures of HIV-1 protease mutants with substrate analogs

FEBS Journal ◽  
2005 ◽  
Vol 272 (20) ◽  
pp. 5265-5277 ◽  
Author(s):  
Yunfeng Tie ◽  
Peter I. Boross ◽  
Yuan-Fang Wang ◽  
Laquasha Gaddis ◽  
Fengling Liu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Crystal Structures ◽  
Molecular Basis ◽  
Substrate Recognition ◽  
Substrate Analogs ◽  
Hiv 1

scholarly journals HIV-1 Vpr Loads Uracil DNA Glycosylase-2 onto DCAF1, a Substrate Recognition Subunit of a Cullin 4A-RING E3 Ubiquitin Ligase for Proteasome-dependent Degradation

2010 ◽  
Vol 285 (48) ◽  
pp. 37333-37341 ◽  
Author(s):  
Jinwoo Ahn ◽  
Thomas Vu ◽  
Zach Novince ◽  
Jennifer Guerrero-Santoro ◽  
Vesna Rapic-Otrin ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Substrate Recognition ◽  
E3 Ubiquitin Ligase ◽  
Dna Glycosylase ◽  
Uracil Dna Glycosylase ◽  
Cullin 4A ◽  
Ring E3 ◽  
Hiv 1

scholarly journals Dynamics of Preferential Substrate Recognition in HIV-1 Protease: Redefining the Substrate Envelope

2011 ◽  
Vol 410 (4) ◽  
pp. 726-744 ◽  
Author(s):  
Ayşegül Özen ◽  
Türkan Haliloğlu ◽  
Celia A. Schiffer
Keyword(s):  
Substrate Recognition ◽  
Hiv 1 ◽  
Substrate Envelope

Local and spatial factors determining HIV-1 protease substrate recognition

2001 ◽  
Vol 358 (2) ◽  
pp. 505-510 ◽  
Author(s):  
Stephane HAZEBROUCK ◽  
Valerie MACHTELINCKX-DELMAS ◽  
Jean-Jacques KUPIEC ◽  
Pierre SONIGO
Keyword(s):  
Amino Acids ◽  
Cleavage Site ◽  
Insertional Mutagenesis ◽  
Substrate Recognition ◽  
Enzymic Activity ◽  
Local Sequence ◽  
Protease Substrate ◽  
The Stability ◽  
Potential Cleavage Site ◽  
Hiv 1

Insertional mutagenesis of the Escherichia coli thymidylate synthase (TS) was used to address substrate recognition of HIV-1 protease in a well characterized structural context. By modifying the TS conformation while maintaining its enzymic activity, we investigated the influence of protein folding on protease–substrate recognition. A slight destabilization of the TS structure permitted the cleavage of a target site, which was resistant in the native TS. This result supports a dynamic interpretation of HIV-1 protease specificity. Exposure time of the potential cleavage site, which depends on the stability of the global conformation, must be compatible with the cleavage kinetics, which are determined by the local sequence. Cleavage specificity has been described as the consequence of cumulative interactions, globally favourable, between at least six amino acids around the cleavage site. To investigate influence of local sequence, we introduced insertions of variable lengths in two exposed loops of the TS. In both environments, insertion of only two amino acids could determine specific cleavage. We then inserted libraries of dipeptides naturally cleaved by the HIV-1 protease in order to assess the limitations of established classifications of substrates in different conformational contexts.

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