2X83

Evolutionary basis of HIV restriction by the antiretroviral TRIMCyp

Summary for 2X83

• Entry DOI: 10.2210/pdb2x83/pdb
• Related: 2X82
• Descriptor: HIV-1 CAPSID, TRIM5/CypA fusion protein (3 entities in total)
• Functional Keywords: trim, viral protein, restriction factor immunity
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 4
• Total formula weight: 67923.57

Authors

Price, A.J.,James, L.C. (deposition date: 2010-03-05, release date: 2010-09-15, Last modification date: 2024-05-08)

Primary citation

Ylinen, L.M.,Price, A.J.,Rasaiyaah, J.,Hue, S.,Rose, N.J.,Marzetta, F.,James, L.C.,Towers, G.J.
Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity.
Plos Pathog., 6:e1001062-e1001062, 2010

PubMed Abstract: TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5alpha but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations.

PubMed: 20808866
DOI: 10.1371/journal.ppat.1001062

Experimental method

X-RAY DIFFRACTION (1.7 Å)