6KDM

HIV-1 reverse transcriptase with Q151M/Y115F/F116Y:DNA:entecavir 5'-triphosphate ternary complex

PDB DOI: https://doi.org/10.2210/pdb6KDM/pdb
NAKB: 6KDM

Classification: TRANSFERASE/DNA
Organism(s): Human immunodeficiency virus 1, synthetic construct
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2019-07-02 Released: 2020-03-04
Deposition Author(s): Yasutake, Y., Hattori, S.I., Tamura, N., Maeda, K.
Funding Organization(s): Japan Agency for Medical Research and Development (AMED)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.32 ?
R-Value Free: 0.223
R-Value Work: 0.190
R-Value Observed: 0.192

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Structural features in common of HBV and HIV-1 resistance against chirally-distinct nucleoside analogues entecavir and lamivudine.

Yasutake, Y., Hattori, S.I., Tamura, N., Matsuda, K., Kohgo, S., Maeda, K., Mitsuya, H.

(2020) Sci Rep 10: 3021-3021

PubMed: 32080249 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/s41598-020-59775-w
Primary Citation of Related Structures:
6KDJ, 6KDK, 6KDM, 6KDN, 6KDO

PubMed Abstract:
Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIV ^{Y115F/F116Y/Q151M}) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIV ^{Y115F/F116Y/Q151M} with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RT ^{Y115F/F116Y/Q151M}:DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RT ^{Y115F/F116Y/Q151M/F160M/M184V}:DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain γ-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV.

Organizational Affiliation

Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo, 062-8517, Japan. y-yasutake@aist.go.jp.

Macromolecule Content

Total Structure Weight: 256.87 kDa
Atom Count: 17,780
Modelled Residue Count: 1,991
Deposited Residue Count: 2,078
Unique protein chains: 2
Unique nucleic acid chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
HIV-1 reverse transcriptase p66 subunit	A, D [auth C]	557	Human immunodeficiency virus 1	Mutation(s): 5 Gene Names: pol
UniProt
Find proteins for P12497 (Human immunodeficiency virus type 1 group M subtype B (isolate NY5)) Explore P12497 Go to UniProtKB: P12497
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P12497
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
HIV-1 RT p51 subunit	B, E [auth D]	444	Human immunodeficiency virus 1	Mutation(s): 2
UniProt
Find proteins for P12497 (Human immunodeficiency virus type 1 group M subtype B (isolate NY5)) Explore P12497 Go to UniProtKB: P12497
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P12497
Sequence Annotations Expand
Reference Sequence

Find similar nucleic acids by:

(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Length	Organism	Image
DNA/RNA (38-MER)	C [auth E], F	38	synthetic construct
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
ET9 (Subject of Investigation/LOI) Query on ET9 Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain M [auth C] MOL2 format, chain I [auth A] MOL2 format, chain M [auth C] mmCIF format, chain I [auth A] mmCIF format, chain M [auth C]	I [auth A], M [auth C]	[[(1R,3S,5S)-3-(2-azanyl-6-oxidanylidene-3H-purin-9-yl)-2-methylidene-5-oxidanyl-cyclopentyl]methoxy-oxidanyl-phosphory l] phosphono hydrogen phosphate C₁₂ H₁₈ N₅ O₁₂ P₃ YMBBDUCQYPKKJK-FXQIFTODSA-N		Interactions Focus chain I [auth A] Focus chain M [auth C] Interactions & Density Focus chain I [auth A] Focus chain M [auth C]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain J [auth B] SDF format, chain K [auth E] SDF format, chain N [auth D] SDF format, chain O [auth D] SDF format, chain P [auth D] MOL2 format, chain G [auth A] MOL2 format, chain J [auth B] MOL2 format, chain K [auth E] MOL2 format, chain N [auth D] MOL2 format, chain O [auth D] MOL2 format, chain P [auth D] mmCIF format, chain G [auth A] mmCIF format, chain J [auth B] mmCIF format, chain K [auth E] mmCIF format, chain N [auth D] mmCIF format, chain O [auth D] mmCIF format, chain P [auth D]	G [auth A] J [auth B] K [auth E] N [auth D] O [auth D] G [auth A], J [auth B], K [auth E], N [auth D], O [auth D], P [auth D]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain J [auth B] Focus chain K [auth E] Focus chain N [auth D] Focus chain O [auth D] Focus chain P [auth D] Interactions & Density Focus chain G [auth A] Focus chain J [auth B] Focus chain K [auth E] Focus chain N [auth D] Focus chain O [auth D] Focus chain P [auth D]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain L [auth C] MOL2 format, chain H [auth A] MOL2 format, chain L [auth C] mmCIF format, chain H [auth A] mmCIF format, chain L [auth C]	H [auth A], L [auth C]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain L [auth C] Interactions & Density Focus chain H [auth A] Focus chain L [auth C]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.32 ?
R-Value Free: 0.223
R-Value Work: 0.190
R-Value Observed: 0.192
Space Group: H 3

Unit Cell:

Length ( ? )	Angle ( ? )
a = 284.447	α = 90
b = 284.447	β = 90
c = 95.773	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data reduction
Aimless	data scaling
PHENIX	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2020-03-04

Deposition Author(s):

Funding Organization	Location	Grant Number
Japan Agency for Medical Research and Development (AMED)	Japan	JP19fk0310113

Revision History (Full details and data files)

Version 1.0: 2020-03-04
Type: Initial release
Version 1.1: 2023-11-22
Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary