The US wants the site near the city of Fordo, southwest of Tehran, shut down or converted to a purpose other than uranium enrichment because the plant is dug deep into a mountain.
Because of that, Washington, and Iran's arch-foe Israel, fears the fortified plant is impervious to an air attack.
Centrifuges enriching uranium can churn out material ranging from low-level reactor fuel to the fissile core of a nuclear weapon.
Iran denies it wants nuclear arms and was reportedly engaging on US proposals on reconfiguring the site at previous negotiating rounds.
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But that has changed at the most recent session, which began Friday, said two diplomats, who demanded anonymity because their information is confidential.
They said Tehran now is invoking the case of what they say was an Israel drone they shot down last month near their main enrichment site at Natanz in arguing that they need to leave Fordo as an enrichment plant because of the vulnerability of the Natanz plant, south of Tehran.
Tehran is also pushing members of the UN's International Atomic Energy Agency to condemn Israel over the alleged incident at the IAEA's general assembly this week.
Washington's main aim at the talks is to place strict constraints on the size and output of Iran's uranium enrichment program, and diplomats told the AP last week that it was trying a new approach in attempts to erode Tehran's resistance.
They said a new US proposal on the table focuses on removing piping connecting the centrifuges. That would allow the US leeway on modifying demands that Iran cut the number of centrifuge machines from 19,000 to no more than 1,500.