1HIV

CRYSTAL STRUCTURE OF A COMPLEX OF HIV-1 PROTEASE WITH A DIHYDROETHYLENE-CONTAINING INHIBITOR: COMPARISONS WITH MOLECULAR MODELING

PDB DOI: https://doi.org/10.2210/pdb1HIV/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Human immunodeficiency virus 1
Expression System: Escherichia coli
Mutation(s): No

Deposited: 1992-02-12 Released: 1993-10-31
Deposition Author(s): Thanki, N., Wlodawer, A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Observed: 0.169

wwPDB Validation 3D Report Full Report

This is version 1.4 of the entry. See complete history.

Literature

Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: comparisons with molecular modeling.

Thanki, N., Rao, J.K., Foundling, S.I., Howe, W.J., Moon, J.B., Hui, J.O., Tomasselli, A.G., Heinrikson, R.L., Thaisrivongs, S., Wlodawer, A.

(1992) Protein Sci 1: 1061-1072

PubMed: 1304383 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/pro.5560010811
Primary Citation of Related Structures:
1HIV

PubMed Abstract:
The structure of a crystal complex of recombinant human immunodeficiency virus type 1 (HIV-1) protease with a peptide-mimetic inhibitor containing a dihydroxyethylene isostere insert replacing the scissile bond has been determined. The inhibitor is Noa-His-Hch psi [CH(OH)CH(OH)]Vam-Ile-Amp (U-75875), and its Ki for inhibition of the HIV-1 protease is < 1.0 nM (Noa = 1-naphthoxyacetyl, Hch = a hydroxy-modified form of cyclohexylalanine, Vam = a hydroxy-modified form of valine, Amp = 2-pyridylmethylamine). The structure of the complex has been refined to a crystallographic R factor of 0.169 at 2.0 A resolution by using restrained least-squares procedures. Root mean square deviations from ideality are 0.02 A and 2.4 degrees, for bond lengths and angles, respectively. The bound inhibitor diastereomer has the R configurations at both of the hydroxyl chiral carbon atoms. One of the diol hydroxyl groups is positioned such that it forms hydrogen bonds with both the active site aspartates, whereas the other interacts with only one of them. Comparison of this X-ray structure with a model-built structure of the inhibitor, published earlier, reveals similar positioning of the backbone atoms and of the side-chain atoms in the P2-P2' region, where the interaction with the protein is strongest. However, the X-ray structure and the model differ considerably in the location of the P3 and P3' end groups, and also in the positioning of the second of the two central hydroxyl groups. Reconstruction of the central portion of the model revealed the source of the hydroxyl discrepancy, which, when corrected, provided a P1-P1' geometry very close to that seen in the X-ray structure.

Organizational Affiliation

Macromolecular Structure Laboratory, NCI-Frederick Cancer Research and Development Center, ABL-Basic Research Program, Maryland 21702.

Macromolecule Content

Total Structure Weight: 22.42 kDa
Atom Count: 1,665
Modelled Residue Count: 198
Deposited Residue Count: 198
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
HIV-1 PROTEASE	A, B	99	Human immunodeficiency virus 1	Mutation(s): 0
UniProt
Find proteins for P04585 (Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)) Explore P04585 Go to UniProtKB: P04585
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P04585
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
1ZK Query on 1ZK Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	4-[(2R)-3-{[(1S,2S,3R,4S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-({(1S,2R)-2-methyl-1-[(pyridin-2-ylmethyl)carba moyl]butyl}carbamoyl)hexyl]amino}-2-{[(naphthalen-1-yloxy)acetyl]amino}-3-oxopropyl]-1H-imidazol-3-ium C₄₅ H₆₂ N₇ O₇ ZTKCGLWIXHAITR-JIFWBGJESA-O		Interactions Focus chain C [auth A]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
CSO Query on CSO	A, B	L-PEPTIDE LINKING	C₃ H₇ N O₃ S		CYS

Binding Affinity Annotations
ID	Source	Binding Affinity
1ZK	Binding MOAD: 1HIV	Ki: 1 (nM) from 1 assay(s)

Biologically Interesting Molecules (External Reference) 1 Unique

Entity ID: 2
ID	Chains	Name	Type/Class	2D Diagram	3D Interactions
PRD_000403 (1ZK) Query on PRD_000403	C [auth A]	Noa-His-Cha.psi.[CHOHCHOH]Val-Ile-Amp, U75875	Peptide-like / Inhibitor		Interactions Focus chain C [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Observed: 0.169
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 52	α = 90
b = 58.6	β = 90
c = 61.9	γ = 90

Software Package:

Software Name	Purpose
PROLSQ	refinement

Structure Validation

View Full Validation Report

Entry History

Deposition Data

Released Date: 1993-10-31

Deposition Author(s):

Thanki, N.

Wlodawer, A.

Revision History (Full details and data files)

Version 1.0: 1993-10-31
Type: Initial release
Version 1.1: 2008-03-03
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
Version 1.3: 2012-12-12
Changes: Other
Version 1.4: 2017-11-29
Changes: Derived calculations, Other