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- PDB-1hvh: NONPEPTIDE CYCLIC CYANOGUANIDINES AS HIV PROTEASE INHIBITORS -

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Basic information

Entry
Database: PDB / ID: 1hvh
TitleNONPEPTIDE CYCLIC CYANOGUANIDINES AS HIV PROTEASE INHIBITORS
ComponentsHIV-1 PROTEASE
KeywordsACID PROTEASE / HYDROLASE
Function / homology
Function and homology information


integrase activity / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / 2-LTR circle formation / Vpr-mediated nuclear import of PICs / Early Phase of HIV Life Cycle / Integration of provirus ...integrase activity / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / 2-LTR circle formation / Vpr-mediated nuclear import of PICs / Early Phase of HIV Life Cycle / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / Binding and entry of HIV virion / viral life cycle / HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / Assembly Of The HIV Virion / Budding and maturation of HIV virion / host multivesicular body / protein processing / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / viral penetration into host nucleus / RNA stem-loop binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / peptidase activity / host cell / viral nucleocapsid / DNA recombination / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase activity / symbiont-mediated suppression of host gene expression / viral translational frameshifting / lipid binding / symbiont entry into host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / DNA binding / zinc ion binding / identical protein binding / membrane
Similarity search - Function
Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain ...Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / RNase H / Integrase core domain / Integrase, catalytic core / Integrase catalytic domain profile. / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / RNase H type-1 domain profile. / Ribonuclease H domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / Retrovirus capsid, C-terminal / Retroviral matrix protein / Cathepsin D, subunit A; domain 1 / Acid Proteases / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-Q82 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / Resolution: 1.8 Å
AuthorsChang, C.-H.
CitationJournal: J.Med.Chem. / Year: 1998
Title: Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies.
Authors: Jadhav, P.K. / Woerner, F.J. / Lam, P.Y. / Hodge, C.N. / Eyermann, C.J. / Man, H.W. / Daneker, W.F. / Bacheler, L.T. / Rayner, M.M. / Meek, J.L. / Erickson-Viitanen, S. / Jackson, D.A. / ...Authors: Jadhav, P.K. / Woerner, F.J. / Lam, P.Y. / Hodge, C.N. / Eyermann, C.J. / Man, H.W. / Daneker, W.F. / Bacheler, L.T. / Rayner, M.M. / Meek, J.L. / Erickson-Viitanen, S. / Jackson, D.A. / Calabrese, J.C. / Schadt, M. / Chang, C.H.
History
DepositionDec 13, 1997Processing site: BNL
Revision 1.0Dec 30, 1998Provider: repository / Type: Initial release
Revision 1.1Mar 24, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Nov 29, 2017Group: Derived calculations / Other
Category: pdbx_database_status / struct_conf / struct_conf_type
Item: _pdbx_database_status.process_site
Revision 1.4Aug 9, 2023Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HIV-1 PROTEASE
B: HIV-1 PROTEASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1063
Polymers21,5152
Non-polymers5911
Water2,072115
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4870 Å2
ΔGint-32 kcal/mol
Surface area9170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.220, 63.220, 83.680
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

#1: Protein HIV-1 PROTEASE


Mass: 10757.664 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Q8261 OF DUPONT MERCK AS INHIBITOR / Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Variant: BH102 ISOLATE / Production host: Escherichia coli (E. coli) / References: UniProt: P04585, HIV-1 retropepsin
#2: Chemical ChemComp-Q82 / {[4-R(-4-ALPHA,5-ALPHA,6-BETA,7-BETA)]-HEXAHYDRO-5,6-BIS(HYDROXY)-1,3-BIS(4-HYDROXYMETHYL)METHYL]-4,7-BIS(PHENYLMETHYL) -2H-1,3-DIAZEPIN-2-YLIDENE]CYANAMIDE} / Q8261


Mass: 590.711 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H38N4O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 115 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.24 Å3/Da / Density % sol: 45.15 %
Crystal grow
*PLUS
Temperature: 18 ℃ / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
11 mg/mlprotease1drop
2250 mMacetate1drop
3100 mMammonium sulfate1drop
4inhibitor1drop5000-fold molar excess over the Ki value of the inhibitor

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Data collection

RadiationScattering type: x-ray
Radiation wavelengthRelative weight: 1
Reflection
*PLUS
Highest resolution: 1.8 Å / Num. obs: 16515 / % possible obs: 90 % / Num. measured all: 69844 / Rmerge(I) obs: 0.08

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Processing

Software
NameClassification
X-PLORmodel building
X-PLORrefinement
X-PLORphasing
RefinementStarting model: 1HVR

1hvr


Rfactor Rwork: 0.188 / Rfactor obs: 0.188 / Highest resolution: 1.8 Å
Details: THERE ARE TWO BINDING MODES OF INHIBITOR AND CORRESPONDING CONFORMATIONS OF FLAP, RESIDUE 45-54. EACH MATCHING CONFORMATION IS DESIGNATED AS "A" OR "B" IN COLUMN 17 OF THE ATOM RECORDS. ...Details: THERE ARE TWO BINDING MODES OF INHIBITOR AND CORRESPONDING CONFORMATIONS OF FLAP, RESIDUE 45-54. EACH MATCHING CONFORMATION IS DESIGNATED AS "A" OR "B" IN COLUMN 17 OF THE ATOM RECORDS. OCCUPANCY OF THESE WAS SET AT 0.5 AND WAS NOT REFINED.
Refinement stepCycle: LAST / Highest resolution: 1.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1648 0 88 115 1851
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.013
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg2.6
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_scangle_it
Software
*PLUS
Name: X-PLOR / Classification: refinement
Refinement
*PLUS
Solvent computation
*PLUS
Displacement parameters
*PLUS

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