9BXD | pdb_00009bxd

CRYSTAL STRUCTURE OF HIV-1 LM/HS CLADE A/E CRF01 GP120 CORE IN COMPLEX WITH HZ-IV-188

PDB DOI: https://doi.org/10.2210/pdb9BXD/pdb

Classification: VIRAL PROTEIN
Organism(s): Human immunodeficiency virus 1
Expression System: Homo sapiens
Mutation(s): Yes

Deposited: 2024-05-22 Released: 2025-04-02
Deposition Author(s): Niu, L., Tolbert, W.D., Pazgier, M.
Funding Organization(s): National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.85 Å
R-Value Free:
0.259 (Depositor), 0.256 (DCC)
R-Value Work:
0.230 (Depositor), 0.230 (DCC)
R-Value Observed:
0.231 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.0 of the entry. See complete history.

Literature

Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity.

Lee, D., Niu, L., Ding, S., Zhu, H., Tolbert, W.D., Medjahed, H., Beaudoin-Bussieres, G., Abrams, C., Finzi, A., Pazgier, M., Smith 3rd, A.B.

(2024) ACS Med Chem Lett 15: 1961-1969

PubMed: 39563795 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.4c00403
Primary Citation of Related Structures:
9BXB, 9BXD, 9BXF, 9BXG, 9BXW, 9BXY

PubMed Abstract:
The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 protects infected cells from antibody-dependent cellular cytotoxicity (ADCC) by limiting the exposure of vulnerable epitopes to envelope glycoprotein (Env). Small-molecule CD4 mimetics (CD4mcs) based on piperidine scaffolds represent a new family of agents capable of sensitizing HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes on Env that are recognized by non-neutralizing antibodies which are abundant in plasma of people living with HIV. Here, we employed the combined methods of parallel synthesis, structure-based design, and optimization to generate a new line of piperidine-based CD4mcs, which sensitize HIV-1 infected cells to ADCC activity. The X-ray crystallographic study of the CD4mcs within the gp120 residues suggests that the positioning of the CD4mc inside the Phe43 cavity and synergistic contact of the CD4mc with the β _20-21 loop and the α ₁-helix lead to improved antiviral activity.

Organizational Affiliation

Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

Macromolecule Content

Total Structure Weight: 42.33 kDa
Atom Count: 3,024
Modelled Residue Count: 339
Deposited Residue Count: 355
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
HIV-1 LM/HS clade A/E CRF01 gp120 core	A	355	Human immunodeficiency virus 1	Mutation(s): 7 Gene Names: HIV-1 Env
UniProt
Find proteins for A0A0M3KKW9 (Human immunodeficiency virus type 1) Explore A0A0M3KKW9 Go to UniProtKB: A0A0M3KKW9
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A0A0M3KKW9
Glycosylation
Glycosylation Sites: 9	Glycosylation Focus chain A
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1ATK (Subject of Investigation/LOI) Query on A1ATK Download Ideal Coordinates CCD File SDF format, chain L [auth A] MOL2 format, chain L [auth A] mmCIF format, chain L [auth A]	L [auth A]	(3S)-1-(4-L-arginylpiperazine-1-carbonyl)-N-(4-chloro-3-fluorophenyl)piperidine-3-carboxamide C₂₃ H₃₄ Cl F N₈ O₃ QLFBZRONRWNWQO-KXBFYZLASA-N		Interactions Focus chain L [auth A] Interactions & Density Focus chain L [auth A]
EPE Query on EPE Download Ideal Coordinates CCD File SDF format, chain K [auth A] MOL2 format, chain K [auth A] mmCIF format, chain K [auth A]	K [auth A]	4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID C₈ H₁₈ N₂ O₄ S JKMHFZQWWAIEOD-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Interactions & Density Focus chain K [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain B [auth A] SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] MOL2 format, chain B [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] mmCIF format, chain B [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A]	B [auth A] C [auth A] D [auth A] E [auth A] F [auth A] B [auth A], C [auth A], D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Interactions & Density Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A]
MPD Query on MPD Download Ideal Coordinates CCD File SDF format, chain M [auth A] MOL2 format, chain M [auth A] mmCIF format, chain M [auth A]	M [auth A]	(4S)-2-METHYL-2,4-PENTANEDIOL C₆ H₁₄ O₂ SVTBMSDMJJWYQN-YFKPBYRVSA-N		Interactions Focus chain M [auth A] Interactions & Density Focus chain M [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.85 Å
R-Value Free: 0.259 (Depositor), 0.256 (DCC)
R-Value Work: 0.230 (Depositor), 0.230 (DCC)
R-Value Observed: 0.231 (Depositor)

Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 61.013	α = 90
b = 65.837	β = 90
c = 90.518	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
HKL-3000	data reduction
HKL-3000	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2025-04-02

Deposition Author(s):

Niu, L.

Tolbert, W.D.

Pazgier, M.

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)	United States	R01 AI174908
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)	United States	P01 AI162242