Database accession: MF7000986
Name: SIV protease with inhibitor SB203386
PDB ID: 1tcw
Experimental method: X-ray (2.40 Å)
Assembly: Homodimer
Source organism: Simian immunodeficiency virus
Primary publication of the structure:
Hoog SS, Towler EM, Zhao B, Doyle ML, Debouck C, Abdel-Meguid SS
Human immunodeficiency virus protease ligand specificity conferred by residues outside of the active site cavity.
(1996) Biochemistry 35: 10279-86
PMID: 8756683
Abstract:
To gain greater understanding of the structural basis of human immunodeficiency virus (HIV) protease ligand specificity, we have crystallized and determined the structures of the HIV-1 protease (Val32Ile, Ile47Val, Val82Ile) triple mutant and simian immunodeficiency virus (SIV) protease in complex with SB203386, a tripeptide analogue inhibitor containing a C-terminal imidazole substituent as an amide bond isostere. SB203386 is a potent inhibitor of HIV-1 protease (Ki = 18 nM) but shows decreased inhibition of the HIV-1 protease (Val32Ile, Ile47Val, Val82Ile) triple mutant (Ki = 112 nM) and SIV protease (Ki = 960 nM). Although SB203386 binds in the active site cavity of the triple mutant in a similar fashion to its binding to the wild-type HIV-1 protease [Abdel-Meguid et al. (1994) Biochemistry 33, 11671], it binds to SIV protease in an unexpected mode showing two inhibitor molecules each binding to half of the active site. Comparison of these two structures and that of the wild-type HIV-1 protease bound to SB203386 reveals that HIV protease ligand specificity is imparted by residues outside of the catalytic pocket, which causes subtle changes in its shape. Furthermore, this work illustrates the importance of structural studies in order to understand the structure-activity relationship (SAR) between related enzymes.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
aspartic-type endopeptidase activity aspartic-type endopeptidase activity
DNA binding DNA binding
DNA-directed DNA polymerase activity DNA-directed DNA polymerase activity
exoribonuclease H activity exoribonuclease H activity
RNA stem-loop binding RNA stem-loop binding
RNA-directed DNA polymerase activity RNA-directed DNA polymerase activity
RNA-DNA hybrid ribonuclease activity RNA-DNA hybrid ribonuclease activity
structural molecule activity structural molecule activity
zinc ion binding zinc ion binding
Biological process:
DNA integration DNA integration
DNA recombination DNA recombination
establishment of integrated proviral latency establishment of integrated proviral latency
proteolysis proteolysis
symbiont entry into host cell symbiont entry into host cell
symbiont-mediated suppression of host gene expression symbiont-mediated suppression of host gene expression
viral genome integration into host DNA viral genome integration into host DNA
viral penetration into host nucleus viral penetration into host nucleus
Cellular component:
host cell host cell
host cell cytoplasm host cell cytoplasm
host cell nucleus host cell nucleus
host cell plasma membrane host cell plasma membrane
membrane membrane
viral nucleocapsid viral nucleocapsid
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, B
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: Gag-Pol polyprotein
Source organism: Simian immunodeficiency virus
Length: 1448 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMGARNSVLSGKKADELEKIRLRPGGKKKYMLKHVVWAANELDRFGLAESLLENKEGCQKILSVLAPLVPTGSENLKSLYNTVCVIWCIHAEEKVKHTEEAKQIVQRHLVMETGTAETMPKTSRPTAPFSGRGGNYPVQQIGGNYTHLPLSPRTLNAWVKLIEEKKFGAEVVSGFQALSEGCLPYDINQMLNCVGDHQAAMQIIRDIINEEAADWDLQHPQQAPQQGQLREPSGSDIAGTTSTVEEQIQWMYRQQNPIPVGNIYRRWIQLGLQKCVRMYNPTNILDVKQGPKEPFQSYVDRFYKSLRAEQTDPAVKNWMTQTLLIQNANPDCKLVLKGLGTNPTLEEMLTACQGVGGPGQKARLMAEALKEALAPAPIPFAAAQQKGPRKPIKCWNCGKEGHSARQCRAPRRQGCWKCGKMDHVMAKCPNRQAGFFRPWPLGKEAPQFPHGSSASGADANCSPRRTSCGSAKELHALGQAAERKQREALQGGDRGFAAPQFSLWRRPVVTAHIEGQPVEVLLDTGADDSIVTGIELGPHYTPKIVGGIGGFINTKEYKNVEIEVLGKRIKGTIMTGDTPINIFGRNLLTALGMSLNLPIAKVEPVKSPLKPGKDGPKLKQWPLSKEKIVALREICEKMEKDGQLEEAPPTNPYNTPTFAIKKKDKNKWRMLIDFRELNRVTQDFTEVQLGIPHPAGLAKRKRITVLDIGDAYFSIPLDEEFRQYTAFTLPSVNNAEPGKRYIYKVLPQGWKGSPAIFQYTMRHVLEPFRKANPDVTLVQYMDDILIASDRTDLEHDRVVLQLKELLNSIGFSSPEEKFQKDPPFQWMGYELWPTKWKLQKIELPQRETWTVNDIQKLVGVLNWAAQIYPGIKTKHLCRLIRGKMTLTEEVQWTEMAEAEYEENKIILSQEQEGCYYQESKPLEATVIKSQDNQWSYKIHQEDKILKVGKFAKIKNTHTNGVRLLAHVIQKIGKEAIVIWGQVPKFHLPVEKDVWEQWWTDYWQVTWIPEWDFISTPPLVRLVFNLVKDPIEGEETYYVDGSCSKQSKEGKAGYITDRGKDKVKVLEQTTNQQAELEAFLMALTDSGPKANIIVDSQYVMGIITGCPTESESRLVNQIIEEMIKKTEIYVAWVPAHKGIGGNQEIDHLVSQGIRQVLFLEKIEPAQEEHSKYHSNIKELVFKFGLPRLVAKQIVDTCDKCHQKGEAIHGQVNSDLGTWQMDCTHLEGKIVIVAVHVASGFIEAEVIPQETGRQTALFLLKLASRWPITHLHTDNGANFASQEVKMVAWWAGIEHTFGVPYNPQSQGVVEAMNHHLKNQIDRIREQANSVETIVLMAVHCMNFKRRGGIGDMTPAERLINMITTEQEIQFQQSKNSKFKNFRVYYREGRDQLWKGPGELLWKGEGAVILKVGTDIKVVPRRKAKIIKDYGGGKEMDSSSHMEDTGEAREVA
UniProtKB AC: P05896 (positions: 498-596)
Coverage: 6%
Name: Gag-Pol polyprotein
Source organism: Simian immunodeficiency virus
Length: 1448 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMGARNSVLSGKKADELEKIRLRPGGKKKYMLKHVVWAANELDRFGLAESLLENKEGCQKILSVLAPLVPTGSENLKSLYNTVCVIWCIHAEEKVKHTEEAKQIVQRHLVMETGTAETMPKTSRPTAPFSGRGGNYPVQQIGGNYTHLPLSPRTLNAWVKLIEEKKFGAEVVSGFQALSEGCLPYDINQMLNCVGDHQAAMQIIRDIINEEAADWDLQHPQQAPQQGQLREPSGSDIAGTTSTVEEQIQWMYRQQNPIPVGNIYRRWIQLGLQKCVRMYNPTNILDVKQGPKEPFQSYVDRFYKSLRAEQTDPAVKNWMTQTLLIQNANPDCKLVLKGLGTNPTLEEMLTACQGVGGPGQKARLMAEALKEALAPAPIPFAAAQQKGPRKPIKCWNCGKEGHSARQCRAPRRQGCWKCGKMDHVMAKCPNRQAGFFRPWPLGKEAPQFPHGSSASGADANCSPRRTSCGSAKELHALGQAAERKQREALQGGDRGFAAPQFSLWRRPVVTAHIEGQPVEVLLDTGADDSIVTGIELGPHYTPKIVGGIGGFINTKEYKNVEIEVLGKRIKGTIMTGDTPINIFGRNLLTALGMSLNLPIAKVEPVKSPLKPGKDGPKLKQWPLSKEKIVALREICEKMEKDGQLEEAPPTNPYNTPTFAIKKKDKNKWRMLIDFRELNRVTQDFTEVQLGIPHPAGLAKRKRITVLDIGDAYFSIPLDEEFRQYTAFTLPSVNNAEPGKRYIYKVLPQGWKGSPAIFQYTMRHVLEPFRKANPDVTLVQYMDDILIASDRTDLEHDRVVLQLKELLNSIGFSSPEEKFQKDPPFQWMGYELWPTKWKLQKIELPQRETWTVNDIQKLVGVLNWAAQIYPGIKTKHLCRLIRGKMTLTEEVQWTEMAEAEYEENKIILSQEQEGCYYQESKPLEATVIKSQDNQWSYKIHQEDKILKVGKFAKIKNTHTNGVRLLAHVIQKIGKEAIVIWGQVPKFHLPVEKDVWEQWWTDYWQVTWIPEWDFISTPPLVRLVFNLVKDPIEGEETYYVDGSCSKQSKEGKAGYITDRGKDKVKVLEQTTNQQAELEAFLMALTDSGPKANIIVDSQYVMGIITGCPTESESRLVNQIIEEMIKKTEIYVAWVPAHKGIGGNQEIDHLVSQGIRQVLFLEKIEPAQEEHSKYHSNIKELVFKFGLPRLVAKQIVDTCDKCHQKGEAIHGQVNSDLGTWQMDCTHLEGKIVIVAVHVASGFIEAEVIPQETGRQTALFLLKLASRWPITHLHTDNGANFASQEVKMVAWWAGIEHTFGVPYNPQSQGVVEAMNHHLKNQIDRIREQANSVETIVLMAVHCMNFKRRGGIGDMTPAERLINMITTEQEIQFQQSKNSKFKNFRVYYREGRDQLWKGPGELLWKGEGAVILKVGTDIKVVPRRKAKIIKDYGGGKEMDSSSHMEDTGEAREVA
UniProtKB AC: P05896 (positions: 498-596)
Coverage: 6%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: Retroviral aspartyl protease
Evidence level: Direct evidence
Evidence coverage: The full structure participates in mutual synergistic folding.
Complex Evidence:
Retroviral aspartyl proteases follow a two-state unfolding behavior in which folded dimers were in equilibrium with unfolded monomers. This model conforms to cases in which protein unfolding and dimer dissociation are cooperative processes in which folded monomers do not exist (PMID:1390732).
Chain A:
N/A
Chain B:
N/A
Surface and contacts features:
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download the CIF file (.cif)
Download this entry's XML file (.xml)
Download this entry's JSON file (.json)
